ubiquinone and Disease-Models--Animal

Mitochondrial function is closely linked to numerous aspects of eye health. Imbalance between the creation of energy and the development of reactive oxygen species (ROS) seems to be the cause of the development of mitochondrial dysfunctions. As a result of this energy deficit, the level of oxidative stress in the eye tissues increases, leading to numerous ophthalmic impairments. It is important to distinguish between primary mitochondrial eye diseases and secondary mitochondrial changes. Primary mitochondrial eye diseases, for example Leber's hereditary optic atrophy (LHON), retinitis pigmentosa and chronic progressive external ophthalmoplegia are caused by direct damage to mitochondrial function induced by defective genes, either located on mitochondrial DNA (mtDNA) or the DNA of the nucleus (nDNA). In contrast, secondary mitochondrial dysfunctions are caused by environmental factors. In recent years, there has been growing evidence that mitochondrial dysfunctions play an important role in many common eye diseases, such as glaucoma, dry eye, diabetic retinopathy, cataract and age-related macular degeneration (AMD). This article summarises current knowledge of mitochondrial dysfunctions and the role of coenzyme Q10 (CoQ10) as a possible treatment option - with a special focus on glaucoma.. Die mitochondriale Funktion ist mit zahlreichen Aspekten der Gesundheit des Auges eng verknüpft. Ursächlich für mitochondriale Dysfunktionen scheint ein Ungleichgewicht zwischen der Bildung von Energie und der Menge an freien Radikalen zu sein. Dadurch kommt es neben einem Energiemangel zu einer erhöhten oxidativen Belastung der betroffenen Augengewebe mit der Folge einer Vielzahl von ophthalmologischen Beeinträchtigungen. Dabei wird zwischen primären und sekundären mitochondrialen Augenerkrankungen unterschieden. Primäre mitochondriale Erkrankungen wie bspw. die Leberʼsche hereditäre Optikusatrophie (LHON), die Retinitis pigmentosa und die chronisch progressive externe Ophthalmoplegie sind die Folge von direkten Schädigungen der mitochondrialen Funktion durch defekte Gene auf der mitochondrialen DNA (mtDNA) oder auf der nukleären DNA (nDNA). Demgegenüber sind sekundäre mitochondriale Dysfunktionen vor allem auf Umwelteinflüsse zurückzuführen. In jüngster Zeit häufen sich Hinweise darauf, dass auch mitochondriale Dysfunktionen bei vielen häufig auftretenden Augenerkrankungen wie dem Glaukom, dem „Trockenen Auge“, der diabetischen Retinopathie, der Katarakt und der altersabhängigen Makuladegeneration (AMD) eine wichtige Rolle spielen. Dieser Beitrag fasst den derzeitigen Kenntnisstand zu mitochondrialen Dysfunktionen und zur Rolle von Coenzym Q10 (CoQ10) als mögliche Therapieoption beim Glaukom zusammen.

Topics: Animals; Biological Availability; Diagnosis, Differential; Disease Models, Animal; Electron Transport; Energy Metabolism; Eye; Free Radicals; Glaucoma; Humans; Microscopy, Electron; Mitochondrial Diseases; Ophthalmic Solutions; Reactive Oxygen Species; Risk Factors; Ubiquinone

Surveys of patients with multiple sclerosis report that most are interested in modifying their diet and using supplements to potentially reduce the severity and symptoms of the disease. This review provides an updated overview of the current state of evidence for the role that vitamins and dietary supplements play in multiple sclerosis and its animal models, with an emphasis on recent studies, and addresses biological plausibility and safety issues.. Several vitamins and dietary supplements have been recently explored both in animal models and by patients with multiple sclerosis. Most human trials have been small or nonblinded, limiting their generalizability. Biotin and vitamin D are currently being tested in large randomized clinical trials. Smaller trials are ongoing or planned for other supplements such as lipoic acid and probiotics. The results of these studies may help guide clinical recommendations.. At the present time, the only vitamin with sufficient evidence to support routine supplementation for patients with multiple sclerosis is vitamin D. Vitamin deficiencies should be avoided. It is important for clinicians to know which supplements their patients are taking and to educate patients on any known efficacy data, along with any potential medication interactions and adverse effects of individual supplements. Given that dietary supplements and vitamins are not subject to the same regulatory oversight as prescription pharmaceuticals in the United States, it is recommended that vitamins and supplements be purchased from reputable manufacturers with the United States Pharmacopeia designation.

Topics: Acetylcarnitine; Animals; Ascorbic Acid; Biotin; Caffeine; Creatine; Curcumin; Dietary Supplements; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Fatty Acids, Unsaturated; Folic Acid; Ginkgo biloba; Humans; Multiple Sclerosis; Niacin; Pantothenic Acid; Plant Preparations; Probiotics; Pyridoxine; Resveratrol; Riboflavin; Tea; Thiamine; Thioctic Acid; Ubiquinone; Vitamin A; Vitamin B 12; Vitamin D; Vitamin E; Vitamins

Mitochondrial dysfunction characterized by impaired bioenergetics, oxidative stress and aldehydic load is a hallmark of heart failure. Recently, different research groups have provided evidence that selective activation of mitochondrial detoxifying systems that counteract excessive accumulation of ROS, RNS and reactive aldehydes is sufficient to stop cardiac degeneration upon chronic stress, such as heart failure. Therefore, pharmacological and non-pharmacological approaches targeting mitochondria detoxification may play a critical role in the prevention or treatment of heart failure. In this review we discuss the most recent findings on the central role of mitochondrial dysfunction, oxidative stress and aldehydic load in heart failure, highlighting the most recent preclinical and clinical studies using mitochondria-targeted molecules and exercise training as effective tools against heart failure.

Topics: Aldehydes; Animals; Antioxidants; Biomimetic Materials; Cardiotonic Agents; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Energy Metabolism; Exercise; Heart Failure; Humans; Malondialdehyde; Mitochondria, Heart; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Superoxide Dismutase; Ubiquinone

The fruit of the oil palm tree (Elaeis guineesis) is the source of antioxidant-rich red palm oil. Red palm oil is a rich source of phytonutrients such as tocotrienols, tocopherols, carotenoids, phytosterols, squalene, and coenzyme Q10, all of which exhibit nutritional properties and oxidative stability. Mutagenic, nutritional, and toxicological studies have shown that red palm oil contains highly bioavailable β-carotene and vitamin A and is reasonably stable to heat without any adverse effects. This review provides a comprehensive overview of the nutritional properties of red palm oil. The possible antiatherogenic, antihemorrhagic, antihypertensive, anticancer, and anti-infective properties of red palm oil are examined. Moreover, evidence supporting the potential effectiveness of red palm oil to overcome vitamin A deficiency in children and pregnant women, to improve ocular complications of vitamin A deficiency, to protect against ischemic heart disease, to promote normal reproduction in males and females, to aid in the management of diabetes, to ameliorate the adverse effects of chemotherapy, and to aid in managing hypobaric conditions is presented.

Topics: Animals; Antioxidants; Cardiovascular Diseases; Carotenoids; Disease Models, Animal; Evidence-Based Medicine; Fruit; Health Promotion; Humans; Palm Oil; Phytochemicals; Randomized Controlled Trials as Topic; Recommended Dietary Allowances; Squalene; Ubiquinone; Vitamin A Deficiency; Vitamin E

Coenzyme Q(10) is a remarkable lipid involved in many cellular processes such as energy production through the mitochondrial respiratory chain (RC), beta-oxidation of fatty acids, and pyrimidine biosynthesis, but it is also one of the main cellular antioxidants. Its biosynthesis is still incompletely characterized and requires at least 15 genes. Mutations in eight of them (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) cause primary CoQ(10) deficiency, a heterogeneous group of disorders with variable age of onset (from birth to the seventh decade) and associated clinical phenotypes, ranging from a fatal multisystem disease to isolated steroid resistant nephrotic syndrome (SRNS) or isolated central nervous system disease. The pathogenesis is complex and related to the different functions of CoQ(10). It involves defective ATP production and oxidative stress, but also an impairment of pyrimidine biosynthesis and increased apoptosis. CoQ(10) deficiency can also be observed in patients with defects unrelated to CoQ(10) biosynthesis, such as RC defects, multiple acyl-CoA dehydrogenase deficiency, and ataxia and oculomotor apraxia.Patients with both primary and secondary deficiencies benefit from high-dose oral supplementation with CoQ(10). In primary forms treatment can stop the progression of both SRNS and encephalopathy, hence the critical importance of a prompt diagnosis. Treatment may be beneficial also for secondary forms, although with less striking results.In this review we will focus on CoQ(10) biosynthesis in humans, on the genetic defects and the specific clinical phenotypes associated with CoQ(10) deficiency, and on the diagnostic strategies for these conditions.

Topics: Adenosine Triphosphate; Animals; Ataxia; Central Nervous System Diseases; Disease Models, Animal; Electron Transport; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Oxidative Stress; Phenotype; Ubiquinone

Statins inhibit hydroxymethylglutaryl-coenzyme A reductase, decrease plasma low-density lipoprotein cholesterol and reduce cardiovascular morbidity and mortality. They can also exert adverse effects, mostly affecting skeletal muscle, ranging from mild myalgia to rhabdomyolysis.. Based on a PubMed search until December 2014, this review summarizes studies on statin effects on muscle mitochondrial morphology and function in the context of myopathy.. Possible mechanisms of statin-induced myopathy include lower cholesterol synthesis and production of prenylated proteins, reduced dolichols and increased atrogin-1 expression. Statin-treated patients frequently feature decreased muscle coenzyme Q10 (CoQ10) contents, suggesting that statins might impair mitochondrial function. In cell cultures, statins diminish muscle oxygen consumption, promote mitochondrial permeability transient pore opening and generate apoptotic proteins. Animal models confirm the statin-induced decrease in muscle CoQ10, but reveal no changes in mitochondrial enzyme activities. Human studies yield contradictory results, with decreased CoQ10, elevated lipids, decreased enzyme activities in muscle and impaired maximal oxygen uptake in several but not all studies. Some patients are susceptible to statin-induced myopathy due to variations in genes encoding proteins involved in statin uptake and biotransformation such as the solute carrier organic anion transporter family member 1B1 (SLCO1B1) or cytochrome P450 (CYP2D6, CYP3A4, CYP3A5). Carriers for carnitine palmitoyltransferase II deficiency and McArdle disease also present with higher prevalence of statin-induced myopathy.. Despite the widespread use of statins, the pathogenesis of statin-induced myopathy remains unclear, requiring prospective randomized controlled trials with intensive phenotyping also for identifying strategies for its risk assessment, prevention and treatment.

Topics: Animals; Cell Line; Disease Models, Animal; Energy Metabolism; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mitochondria, Muscle; Muscle, Skeletal; Muscular Diseases; Rabbits; Rats; Risk Factors; Ubiquinone

Coenzyme Q, or ubiquinone, is an endogenously synthesized lipid-soluble antioxidant that plays a major role in the mitochondrial respiratory chain. Although extensively studied for decades, recent data on coenzyme Q have painted an exciting albeit incomplete picture of the multiple facets of this molecule's function. In humans, mutations in the genes involved in the biosynthesis of coenzyme Q lead to a heterogeneous group of rare disorders, with most often severe and debilitating symptoms. In this review, we describe the current understanding of coenzyme Q biosynthesis, provide a detailed overview of human coenzyme Q deficiencies and discuss the existing mouse models for coenzyme Q deficiency. Furthermore, we briefly examine the current state of affairs in non-mitochondrial coenzyme Q functions and the latter's link to statin.

Topics: Animals; Ataxia; Disease Models, Animal; Gene Expression Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Mice; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquinone

Huntington's disease (HD) is a prototypical dominantly inherited neurodegenerative disorder characterized by progressive cognitive deterioration, psychiatric disturbances, and a movement disorder. The genetic cause of the illness is a CAG repeat expansion in the huntingtin gene, which leads to a polyglutamine expansion in the huntingtin protein. The exact mechanism by which mutant huntingtin causes HD is unknown, but it causes abnormalities in gene transcription as well as both mitochondrial dysfunction and oxidative damage. Because the penetrance of HD is complete with CAG repeats greater than 39, patients can be diagnosed well before disease onset with genetic testing. Longitudinal studies of HD patients before disease onset have shown that subtle cognitive and motor deficits occur as much as 10 years before onset, as do reductions in glucose utilization and striatal atrophy. An increase in inflammation, as shown by elevated interleukin-6, occurs approximately 15 years before onset. Detection of these abnormalities may be useful in defining an optimal time for disease intervention to try to slow or halt the degenerative process. Although reducing gene expression with small interfering RNA or short hairpin RNA is an attractive approach, other approaches targeting energy metabolism, inflammation, and oxidative damage may be more easily and rapidly moved into the clinic. The recent PREQUEL study of coenzyme Q10 in presymptomatic gene carriers showed the feasibility of carrying out clinical trials to slow or halt onset of HD. We review both the earliest detectable clinical and laboratory manifestations of HD, as well as potential neuroprotective therapies that could be utilized in presymptomatic HD.

Topics: Animals; Disease Models, Animal; Genetic Testing; Humans; Huntington Disease; Mitochondria; Neuroprotective Agents; Ubiquinone

Many human childhood mitochondrial disorders result from abnormal mitochondrial DNA (mtDNA) and altered bioenergetics. These abnormalities span most of the mtDNA, demonstrating that there are no "unique" positions on the mitochondrial genome that when deleted or mutated produce a disease phenotype. This diversity implies that the relationship between mitochondrial genotype and clinical phenotype is very complex. The origins of clinical phenotypes are thus unclear, fundamentally difficult-to-treat, and are usually clinically devastating. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and mortality. Vitamin supplements and pharmacological agents have been used in isolated cases and clinical trials, but the efficacy of these interventions is unclear. In spite of recent advances in the understanding of the pathogenesis of mitochondrial diseases, a cure remains elusive. An optimal cure would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. This review aims to focus on current treatment options and future therapeutics in mitochondrial disease treatment with a special emphasis on Leber's hereditary optic neuropathy.

Topics: Animals; Antioxidants; Dietary Supplements; Disease Models, Animal; DNA-Binding Proteins; DNA, Mitochondrial; Female; Genetic Therapy; Humans; Male; Mitochondria; Mitochondrial Proteins; Mutation; Optic Atrophy, Hereditary, Leber; Oxidative Stress; Phenotype; Recombinant Proteins; Transcription Factors; Ubiquinone

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion of CAG repeats in the HD gene encoding for huntingtin (Htt), resulting in progressive death of striatal neurons, with clinical symptoms of chorea, dementia and dramatic weight loss. Metabolic and mitochondrial dysfunction caused by the expanded polyglutamine sequence have been described along with other mechanisms of neurodegeneration previously described in human tissues and animal models of HD. In this review, we focus on mitochondrial and metabolic disturbances affecting both the central nervous system and peripheral cells, including mitochondrial DNA damage, mitochondrial complexes defects, loss of calcium homeostasis and transcriptional deregulation. Glucose abnormalities have also been described in peripheral tissues of HD patients and in HD animal and cellular models. Moreover, there are no effective neuroprotective treatments available in HD. Thus, we briefly discuss the role of creatine and coenzyme Q10 that target mitochondrial dysfunction and impaired bioenergetics and have been previously used in HD clinical trials.

Topics: Animals; Creatine; Disease Models, Animal; Humans; Huntington Disease; Metabolic Diseases; Mitochondrial Diseases; Nerve Tissue; Ubiquinone

As mitochondrial oxidative damage contributes to a wide range of human diseases, antioxidants designed to be accumulated by mitochondria in vivo have been developed. The most extensively studied of these mitochondria-targeted antioxidants is MitoQ, which contains the antioxidant quinone moiety covalently attached to a lipophilic triphenylphosphonium cation. MitoQ has now been used in a range of in vivo studies in rats and mice and in two phase II human trials. Here, we review what has been learned from these animal and human studies with MitoQ.

Topics: Administration, Oral; Animals; Antioxidants; Cations; Clinical Trials, Phase II as Topic; Disease Models, Animal; Fatty Liver; Humans; Liver Diseases; Mice; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Rats; Treatment Outcome; Ubiquinone

Currently, assessment of new drug efficacy in glaucoma relies on conventional perimetry to monitor visual field changes. However, visual field defects cannot be detected until 20-40% of retinal ganglion cells (RGCs), the key cells implicated in the development of irreversible blindness in glaucoma, have been lost. We have recently developed a new, noninvasive real-time imaging technology, which is named DARC (detection of apoptosing retinal cells), to visualize single RGC undergoing apoptosis, the earliest sign of glaucoma. Utilizing fluorescently labeled annexin 5 and confocal laser scanning ophthalmoscopy, DARC enables evaluation of treatment effectiveness by monitoring RGC apoptosis in the same living eye over time. Using DARC, we have assessed different neuroprotective therapies in glaucoma-related animal models and demonstrated DARC to be a useful tool in screening neuroprotective strategies. DARC will potentially provide a meaningful clinical end point that is based on the direct assessment of the RGC death process, not only being useful in assessing treatment efficacy, but also leading to the early identification of patients with glaucoma. Clinical trials of DARC in glaucoma patients are due to start in 2008.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Clinical Trials as Topic; Disease Models, Animal; Glaucoma; Glutamic Acid; Humans; Lasers; Neuroprotective Agents; Ophthalmoscopes; Ophthalmoscopy; Retinal Ganglion Cells; Ubiquinone; Visual Field Tests; Visual Fields; Vitamins

Since the identification of the genetic mutation causing Friedreich's ataxia (FRDA) our understanding of the mechanisms underlying disease pathogenesis have improved markedly. The genetic abnormality results in the deficiency of frataxin, a protein targeted to the mitochondrion. There is extensive evidence that mitochondrial respiratory chain dysfunction, oxidative damage and iron accumulation play significant roles in the disease mechanism. There remains considerable debate as to the normal function of frataxin, but it is likely to be involved in mitochondrial iron handling, antioxidant regulation, and/or iron sulphur centre regulation. Therapeutic avenues for patients with FRDA are beginning to be explored in particular targeting antioxidant protection, enhancement of mitochondrial oxidative phosphorylation, iron chelation and more recently increasing FRDA transcription. The use of quinone therapy has been the most extensively studied to date with clear benefits demonstrated using evaluations of both disease biomarkers and clinical symptoms, and this is the topic that will be covered in this review.

Topics: Animals; Ataxia; Benzoquinones; Coenzymes; Disease Models, Animal; Friedreich Ataxia; Humans; Iron; Mutation; Neurodegenerative Diseases; Oxidative Stress; Oxygen; Quinones; Time Factors; Ubiquinone; Vitamin E

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta, and in other sub-cortical nuclei associated with a widespread occurrence of Lewy bodies. The cause of cell death in Parkinson's disease is still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative and nitrative stresses have been proposed. We have studied control(wt) (C57B1/6), metallothionein transgenic (MTtrans), metallothionein double gene knock (MTdko), alpha-synuclein knock out (alpha-syn(ko)), alpha-synuclein-metallothionein triple knock out (alpha-syn-MTtko), weaver mutant (wv/wv) mice, and Ames dwarf mice to examine the role of peroxynitrite in the etiopathogenesis of Parkinson's disease and aging. Although MTdko mice were genetically susceptible to 1, methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) Parkinsonism, they did not exhibit any overt clinical symptoms of neurodegeneration and gross neuropathological changes as observed in wv/wv mice. Progressive neurodegenerative changes were associated with typical Parkinsonism in wv/wv mice. Neurodegenerative changes in wv/wv mice were observed primarily in the striatum, hippocampus and cerebellum. Various hallmarks of apoptosis including caspase-3, TNFalpha, NFkappaB, metallothioneins (MT-1, 2) and complex-1 nitration were increased; whereas glutathione, complex-1, ATP, and Ser(40)-phosphorylation of tyrosine hydroxylase, and striatal 18F-DOPA uptake were reduced in wv/wv mice as compared to other experimental genotypes. Striatal neurons of wv/wv mice exhibited age-dependent increase in dense cored intra-neuronal inclusions, cellular aggregation, proto-oncogenes (c-fos, c-jun, caspase-3, and GAPDH) induction, inter-nucleosomal DNA fragmentation, and neuro-apoptosis. MTtrans and alpha-Syn(ko) mice were genetically resistant to MPTP-Parkinsonism and Ames dwarf mice possessed significantly higher concentrations of striatal coenzyme Q10 and metallothioneins (MT 1, 2) and lived almost 2.5 times longer as compared to control(wt) mice. A potent peroxynitrite ion generator, 3-morpholinosydnonimine (SIN-1)-induced apoptosis was significantly attenuated in MTtrans fetal stem cells. These data are interpreted to suggest that peroxynitrite ions are involved in the etiopathogenesis of Parkinson's disease, and metallothionein-mediated coenzyme Q10 synthesis may provide neuroprotection.

Topics: alpha-Synuclein; Animals; Apoptosis; Brain; Coenzymes; Disease Models, Animal; Dopamine; Gene Expression Regulation; Humans; Metallothionein; Mice; Mice, Neurologic Mutants; Mice, Transgenic; MPTP Poisoning; Nerve Tissue Proteins; Parkinson Disease; Synucleins; Ubiquinone

The pathogenesis of Parkinson's disease (PD) remains obscure, but there is increasing evidence that impairment of mitochondrial function, oxidative damage, and inflammation are contributing factors. The present paper reviews the experimental and clinical evidence implicating these processes in PD. There is substantial evidence that there is a deficiency of complex I activity of the mitochondrial electron transport chain in PD. There is also evidence for increased numbers of activated microglia in both PD postmortem tissue as well as in animal models of PD. Impaired mitochondrial function and activated microglia may both contribute to oxidative damage in PD. A number of therapies targeting inflammation and mitochondrial dysfunction are efficacious in the MPTP model of PD. Of these, coenzyme Q(10) appears to be particularly promising based on the results of a recent phase 2 clinical trial in which it significantly slowed the progression of PD.

Topics: Animals; Anti-Inflammatory Agents; Coenzymes; Creatine; Disease Models, Animal; Free Radicals; Humans; Inflammation; Mitochondria; Oxidative Stress; Parkinson Disease; Ubiquinone

Research conducted over the past 10 years has uncovered molecular mechanisms that are likely to be important in the early stages of Huntington's disease pathogenesis. This review summarizes the resources and strategies that are in place in order to exploit these new findings and use them to develop novel Huntington's disease therapeutics. The role that disease models will play in this process is discussed.. A wide variety of models of Huntington's disease have been developed including yeast, Caenorhabditis elegans, Drosophila melanogaster and mouse. These can be developed as screening assays for the identification of chemical compounds that show beneficial effects against a specific phenotype and for the cross validation of potential therapeutics. The first compounds arising through this drug development pipeline have been reported. Similarly, the preclinical screening of compounds in mouse models is being developed in a coordinated manner.. Our understanding of the molecular basis of Huntington's disease is increasing at an exponential rate. Over the next few years an increasing number of potential therapeutic compounds will have been identified. It will only be possible to take a small number of these through to phase III clinical trials. The challenge will be to use the in-vivo models of Huntington's disease to best predict which of these compounds should be pursued in the clinic, to avoid depleting the patient population willing to enter into trials, and demoralizing them by conducting repeated unsuccessful trials.

Topics: Acetamides; Animals; Antioxidants; Creatine; Disease Models, Animal; Evaluation Studies as Topic; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuroprotective Agents; Nuclear Proteins; Peptides; Point Mutation; Riluzole; Thioctic Acid; Trinucleotide Repeats; Ubiquinone

The concepts of energy dysregulation and oxidative stress and their complicated interdependence have rapidly evolved to assume primary importance in understanding the pathophysiology of numerous neurological disorders. Therefore, neuroprotective strategies addressing specific bioenergetic defects hold particular promise in the treatment of these conditions (i.e., amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Friedreich's ataxia, mitochondrial cytopathies and other neuromuscular diseases), all of which, to some extent, share 'the final common pathway' leading to cell death through either necrosis or apoptosis. Compounds such as creatine monohydrate and coenzyme Q(10) offer substantial neuroprotection against ischaemia, trauma, oxidative damage and neurotoxins. Miscellaneous agents, including alpha-lipoic acid, beta-OH-beta-methylbutyrate, riboflavin and nicotinamide, have also been shown to improve various metabolic parameters in brain and/or muscle. This review will highlight the biological function of each of the above mentioned compounds followed by a discussion of their utility in animal models and human neurological disease. The balance of this work will be comprised of discussions on the therapeutic applications of creatine and coenzyme Q(10).

Topics: Amyotrophic Lateral Sclerosis; Animals; Coenzymes; Creatine; Disease Models, Animal; Energy Metabolism; Humans; Huntington Disease; Nervous System Diseases; Neuroprotective Agents; Ubiquinone

Topics: Animals; Coenzymes; Cricetinae; Disease Models, Animal; Female; Follow-Up Studies; Heart Failure; Heart Function Tests; Hemodynamics; Humans; Male; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Severity of Illness Index; Survival Analysis; Treatment Outcome; Ubiquinone

Huntington's disease (HD) is a prototypical neurodegenerative disease characterized by selective loss of neurons in the basal ganglia. Although the gene defect has recently been identified, the mechanism by which it leads to neuronal degeneration remains unknown. We have hypothesized that a defect in oxidative phosphorylation may lead to slow, excitotoxic neuronal degeneration in this illness. Evidence for such a defect is reviewed here, including our recent studies using magnetic resonance imaging spectroscopy that show elevated lactate levels in the basal ganglia and cerebral cortex of patients with HD. If a defect in energy metabolism is responsible for neuronal degeneration in HD, it should be possible to mimic the neurodegenerative process with mitochondrial toxins. Our recent studies with 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase, show that it can produce striking similarities to the neuropathologic and neurochemical features of HD in both rodents and primates. If such a mechanism is indeed relevant to the pathogenesis of HD, then agents that can improve oxidative phosphorylation might prove to be efficacious. We found that both coenzyme Q10 and nicotinamide can ameliorate striatal lesions produced by mitochondrial toxins in vivo. Furthermore, they reduced elevated lactate concentrations when administered to patients with HD. This finding raises the possibility that such an approach might prove useful in trying to slow the neurodegenerative process.

Topics: Animals; Coenzymes; Disease Models, Animal; Energy Metabolism; Humans; Huntington Disease; Mitochondria; Neurotoxins; Niacinamide; Nitro Compounds; Propionates; Ubiquinone

Niemann-Pick disease, type C1 (NPC1), which arises from a mutation in the NPC1 gene, is characterized by abnormal cellular storage and transport of cholesterol and other lipids that leads to hepatic disease and progressive neurological impairment. Oxidative stress has been hypothesized to contribute to the NPC1 disease pathological cascade. To determine whether treatments reducing oxidative stress could alleviate NPC1 disease phenotypes, the in vivo effects of the antioxidant N-acetylcysteine (NAC) on two mouse models for NPC1 disease were studied. NAC was able to partially suppress phenotypes in both antisense-induced (NPC1ASO) and germline (Npc1-/-) knockout genetic mouse models, confirming the presence of an oxidative stress-related mechanism in progression of NPC1 phenotypes and suggesting NAC as a potential molecule for treatment. Gene expression analyses of NAC-treated NPC1ASO mice suggested NAC affects pathways distinct from those initially altered by Npc1 knockdown, data consistent with NAC achieving partial disease phenotype suppression. In a therapeutic trial of short-term NAC administration to NPC1 patients, no significant effects on oxidative stress in these patients were identified other than moderate improvement of the fraction of reduced CoQ10, suggesting limited efficacy of NAC monotherapy. However, the mouse model data suggest that the distinct antioxidant effects of NAC could provide potential treatment of NPC1 disease, possibly in concert with other therapeutic molecules at earlier stages of disease progression. These data also validated the NPC1ASO mouse as an efficient model for candidate NPC1 drug screening, and demonstrated similarities in hepatic phenotypes and genome-wide transcript expression patterns between the NPC1ASO and Npc1-/- models.

Topics: Acetylcysteine; Adolescent; Adult; Animals; Child; Child, Preschool; Cross-Over Studies; Disease Models, Animal; Double-Blind Method; Female; Gene Expression; Humans; Liver; Male; Mice; Mice, Knockout; Niemann-Pick Disease, Type C; Oxidative Stress; Ubiquinone; Young Adult

Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Antioxidants; Biomarkers; Blotting, Western; Disease Models, Animal; DNA Primers; Enzyme-Linked Immunosorbent Assay; Fluorescein-5-isothiocyanate; Genotype; Glomerular Filtration Rate; Humans; Immunohistochemistry; Kidney Tubules, Proximal; Methylmalonyl-CoA Mutase; Mice; Mice, Knockout; Microarray Analysis; Microscopy, Electron, Transmission; Nephritis, Interstitial; Real-Time Polymerase Chain Reaction; Transgenes; Ubiquinone

To explore the presence and consequences of tissue hypoxia in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).. EAE was induced in Dark Agouti rats by immunization with recombinant myelin oligodendrocyte glycoprotein and adjuvant. Tissue hypoxia was assessed in vivo using 2 independent methods: an immunohistochemical probe administered intravenously, and insertion of a physical, oxygen-sensitive probe into the spinal cord. Indirect markers of tissue hypoxia (eg, expression of hypoxia-inducible factor-1α [HIF-1α], vessel diameter, and number of vessels) were also assessed. The effects of brief (1 hour) and continued (7 days) normobaric oxygen treatment on function were evaluated in conjunction with other treatments, namely administration of a mitochondrially targeted antioxidant (MitoQ) and inhibition of inducible nitric oxide synthase (1400W).. Observed neurological deficits were quantitatively, temporally, and spatially correlated with spinal white and gray matter hypoxia. The tissue expression of HIF-1α also correlated with loss of function. Spinal microvessels became enlarged during the hypoxic period, and their number increased at relapse. Notably, oxygen administration significantly restored function within 1 hour, with improvement persisting at least 1 week with continuous oxygen treatment. MitoQ and 1400W also caused a small but significant improvement.. We present chemical, physical, immunohistochemical, and therapeutic evidence that functional deficits caused by neuroinflammation can arise from tissue hypoxia, consistent with an energy crisis in inflamed central nervous system tissue. The neurological deficit was closely correlated with spinal white and gray matter hypoxia. This realization may indicate new avenues for therapy of neuroinflammatory diseases such as MS.

Topics: Amidines; Animals; Benzylamines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Micronutrients; Organophosphorus Compounds; Oxygen; Rats; Recovery of Function; Severity of Illness Index; Single-Blind Method; Spinal Cord Diseases; Ubiquinone

Between 82.8% and 92.5% of participants in any BMI group were responders by AS, and between 91.3% and 100% were responders by BBPS in the right colon. Efficacy was consistent across BMI groups, with no clear trends. Greater than 83% of participants in any BMI group found the preparation 'easy' or 'acceptable' to ingest, and the majority (>58%) rated SPMC oral solution as 'better' than a prior bowel preparation. In all BMI groups, safety data were similar to the overall cohort. Commonly reported, drug-related, treatment-emergent AEs were, by ascending BMI group, nausea (1.1%, 5.3%, 1.0%, 5.7%, and 0%) and headache (1.1%, 4.1%, 1.0%, 5.7%, and 0%).. Ready-to-drink SPMC oral solution had consistent, good quality colon cleansing, and favorable tolerability among participants of all BMI groups.. NCT03017235.. The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.. Of the 98 patients included in the study, 58 had CR (59%), 28 had PR (29%), and 12 patients had NR (12%). The percent splenic tissue embolized was significantly greater in the CR group compared to the PR group (P = 0.001). The percent volume of splenic tissue embolized was linearly correlated with the magnitude of platelet increase without a minimum threshold. At least one line of chemotherapy was successfully restarted in 97% of patients, and 41% of patients did not experience recurrence of thrombocytopenia for the duration of their survival. The major complication rate was 8%, with readmission following initial hospitalization for persistent "post-embolization syndrome" symptoms the most common.. In cancer patients with hypersplenism-related thrombocytopenia, PSAE is a safe intervention that effects a durable elevation in platelet counts across a range of malignancies and following the re-initiation of chemotherapy.. Postoperative CRP elevation was a better predictor of prognosis in patients with gastric cancer than the occurrence of intra-abdominal infectious complications.. In clinical practice, mixed-species malaria infections are often not detected by light microscopy (LM) or rapid diagnostic test, as a low number of parasites of one species may occur. Here, we report the case of an 8-year-old girl migrating with her family from Afghanistan with a two-species mixed infection with

Topics: 3-Hydroxybutyric Acid; Acetazolamide; Acrylates; Administration, Intravenous; Adolescent; Adult; Aerosols; Afghanistan; Aflatoxin M1; Agaricales; Aged; Aged, 80 and over; Agricultural Irrigation; Air Pollutants; alpha-L-Fucosidase; Amino Acid Sequence; Androgen Antagonists; Animals; Antibodies, Bacterial; Antigens, Bacterial; Antineoplastic Agents; Antioxidants; Apoptosis; Artifacts; Autophagy; B7-H1 Antigen; Bacterial Proteins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Bile; Bioelectric Energy Sources; Biosensing Techniques; Body Mass Index; Brain; Brazil; Breast Neoplasms; Bufo arenarum; Burkholderia; C-Reactive Protein; Cadmium; Carbon Compounds, Inorganic; Carbon-13 Magnetic Resonance Spectroscopy; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Carcinoma, Transitional Cell; Case-Control Studies; CD4-Positive T-Lymphocytes; Cell Count; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Characiformes; Child; China; Cities; Cobalt; Colonic Neoplasms; Copper Sulfate; Cross-Sectional Studies; Cyclin-Dependent Kinase Inhibitor p16; Cytokines; Deoxycytidine; Diagnosis, Differential; Digestive System; Dihydroxyphenylalanine; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferase 1; DNA Barcoding, Taxonomic; DNA, Bacterial; Dose-Response Relationship, Drug; Down-Regulation; Edetic Acid; Electrochemical Techniques; Electrodes; Embolization, Therapeutic; Embryo, Nonmammalian; Environmental Monitoring; Enzyme-Linked Immunosorbent Assay; Epithelial-Mesenchymal Transition; Fatty Acids; Feces; Female; Follow-Up Studies; Food Contamination; Forkhead Box Protein M1; Fresh Water; Fungicides, Industrial; Gallium Isotopes; Gallium Radioisotopes; Gastrectomy; Gastric Bypass; Gastric Outlet Obstruction; Gastroplasty; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, Bacterial; Genetic Markers; Genome, Bacterial; Genome, Mitochondrial; Glioma; Glycogen Synthase Kinase 3 beta; Goats; Gonads; Guatemala; Halomonadaceae; HEK293 Cells; Helicobacter Infections; Helicobacter pylori; Hepacivirus; Histone-Lysine N-Methyltransferase; Hormones; Humans; Hydroxybutyrate Dehydrogenase; Hypersplenism; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Iran; Japan; Lactuca; Laparoscopy; Larva; Ligands; Liver Neoplasms; Lymphocyte Activation; Macrophages; Malaria; Male; Mercury; Metabolic Syndrome; Metals, Heavy; Mice; Middle Aged; Milk, Human; Mitochondria; Models, Molecular; Molecular Structure; Mothers; Multilocus Sequence Typing; Muscles; Mutation; Nanocomposites; Nanotubes, Carbon; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Neuroimaging; Nitriles; Nitrogen Isotopes; Non-alcoholic Fatty Liver Disease; Nuclear Magnetic Resonance, Biomolecular; Obesity; Obesity, Morbid; Oligopeptides; Oxidation-Reduction; Pancreatic Neoplasms; Particle Size; Particulate Matter; Pepsinogen A; Pesticides; Pharmacogenetics; Phosphatidylinositol 3-Kinases; Phospholipids; Phylogeny; Plasmodium ovale; Plasmodium vivax; Platelet Count; Polyhydroxyalkanoates; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postoperative Complications; Pregnancy; Prevalence; Prognosis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Domains; Proto-Oncogene Proteins c-akt; Proton Magnetic Resonance Spectroscopy; Pseudogenes; PTEN Phosphohydrolase; Pyrazoles; Pyrimidines; Radiographic Image Interpretation, Computer-Assisted; Radiopharmaceuticals; Rats, Long-Evans; Rats, Sprague-Dawley; RAW 264.7 Cells; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptor, Notch3; Receptors, G-Protein-Coupled; Receptors, Urokinase Plasminogen Activator; Recombinant Proteins; Repressor Proteins; Resveratrol; Retrospective Studies; Risk Assessment; Risk Factors; RNA, Messenger; RNA, Ribosomal, 16S; Salinity; Salvage Therapy; Seasons; Sequence Analysis, DNA; Seroepidemiologic Studies; Signal Transduction; Skin; Snails; Soluble Guanylyl Cyclase; Solutions; Spain; Species Specificity; Spheroids, Cellular; Splenic Artery; Stomach Neoplasms; Streptococcus pneumoniae; Structure-Activity Relationship; Sulfonamides; Sunlight; Surface Properties; Surgical Instruments; Surgical Wound Infection; Survival Rate; Tetrahydrouridine; Thinness; Thrombocytopenia; Tissue Distribution; Titanium; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Turkey; Ubiquinone; Urologic Neoplasms; Viral Envelope Proteins; Wastewater; Water Pollutants, Chemical; Weather; Wnt Signaling Pathway; Xenograft Model Antitumor Assays; Young Adult

Myocardial stunning, defined as a reversible decrease in contractility after ischemia and reperfusion, may be a manifestation of reperfusion injury caused by free oxygen radical damage. The aim of this study was to test the hypothesis that pretreatment with coenzyme Q10 (ubiquinone), believed to act as a free radical scavenger, reduces myocardial stunning in a porcine model. Twelve swine were randomized to receive either oral supplementation with coenzyme Q10 or placebo for 20 days. A normothermic open-chest model was used with short occlusion (8 min) of the distal left descending coronary artery followed by reperfusion. Regional contractile function was measured with epicardial Doppler crystals in ischemic and nonischemic segments by measuring thickening fraction of the left ventricular wall during systole. Stunning time was defined as the elapsed time of reduced contractility until return to baseline. Coenzyme Q10 concentrations were measured in blood and homogenized myocardial tissue by high performance liquid chromatography. Plasma levels of reduced coenzyme Q10 (ubiquinol) were higher in swine pretreated with the experimental medication as compared to placebo (mean 0.45 mg/l versus 0.11 mg/l, respectively). Myocardial tissue concentrations, however, did not show any changes (mean 0.79 micrograms/mg dry weight versus 0.74 micrograms/mg). Stunning time was significantly reduced in coenzyme Q10 pretreated animals (13.7 +/- 7.7 min versus 32.8 +/- 3.1 min, P < 0.01). In conclusion, chronic pretreatment with coenzyme Q10 protects ischemic myocardium in an open-chest swine model. The beneficial effect of coenzyme Q10 on myocardial stunning may be due to protection from free radical mediated reperfusion injury. This protective effect seems to be generated by a humoral rather than intracellular mechanism.

Topics: Animals; Coenzymes; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Hemodynamics; Myocardial Ischemia; Myocardial Stunning; Random Allocation; Swine; Ubiquinone

No treatment exists for mitochondrial dysfunction, a contributor to end-organ disease in human immunodeficiency virus (HIV). The mitochondrial antioxidant mitoquinone mesylate (MitoQ) attenuates mitochondrial dysfunction in preclinical mouse models of various diseases but has not been used in HIV. We used a humanized murine model of chronic HIV infection and polymerase chain reaction to show that HIV-1-infected mice treated with antiretroviral therapy and MitoQ for 90 days had higher ratios of human and murine mitochondrial to nuclear DNA in end organs compared with HIV-1-infected mice on antiretroviral therapy. We offer translational evidence of MitoQ as treatment for mitochondrial dysfunction in HIV.

Topics: Animals; Antioxidants; Disease Models, Animal; DNA, Mitochondrial; HIV Infections; Humans; Mice; Mitochondria; Organophosphorus Compounds; Ubiquinone

Postoperative adhesion is a common cause of long-term morbidity after abdominal or pelvic surgery. The development of postoperative adhesion involves oxidative stress, inflammatory response, and collagen deposition mechanisms. Here, we demonstrate that mitoquinone could be useful for the treatment of postoperative adhesion.. A murine adhesion model was established by induction of peritoneal ischemic buttons. Mice received different doses of mitoquinone via the tail vein. All the ischemic buttons were dissected at 1 day and 7 days after surgery to investigate the effect of mitoquinone in the early and late stage of the adhesion process, respectively. Human peritoneal mesothelial cells were treated with H. Postoperative adhesion scores were markedly decreased in mitoquinone-treated mice compared with the control mice. The degree of oxidative stress, inflammatory injury, and collagen deposition were also significantly reduced in the mitoquinone-treated mice. The expression of plasminogen-activating inhibitor, interleukin-1, interleukin-6, tumor necrosis factor-α, vascular endothelial growth factor, malondialdehyde, and nitric oxide was decreased, while the expression of tissue-type plasminogen activator, glutathione, superoxide dismutase, and Nrf2 was increased in the peritoneal ischemic buttons after mitoquinone treatment. Cellular reactive oxygen species and the canonical inflammatory pathway were inhibited in mitoquinone-treated human peritoneal mesothelial cells after H. The mitochondria-targeting antioxidant molecule mitoquinone attenuates postoperative adhesion formation by inhibiting oxidative stress, inflammation, and collagen accumulation, and therefore provides a therapeutic agent for the management of surgical adhesion.

Topics: Animals; Antioxidants; Cell Line; Disease Models, Animal; Epithelial Cells; Heme Oxygenase-1; Humans; Male; Membrane Proteins; Mice; Mitochondria; NF-E2-Related Factor 2; Organophosphorus Compounds; Oxidative Stress; Peritoneum; Postoperative Complications; Reactive Oxygen Species; Signal Transduction; Tissue Adhesions; Ubiquinone

Topics: Animals; Disease Models, Animal; Female; Magnesium; Mice; Pharmaceutical Preparations; Praziquantel; Schistosoma mansoni; Schistosomiasis mansoni; Sphingomyelin Phosphodiesterase; Ubiquinone

We aimed to create a mechanical optic nerve damage model in rats and to investigate the neuroprotective effects of topical Coenzyme Q10 + Vitamin E TPGS (CoQ10+Vit E) molecule on retinal ganglion cells. In our study, 30 eyes of 20 male Wistar rats were used. Three groups, each consisting of 10 eyes, were formed as control, experimental, and treatment groups. The control group was used to test the formation of optic nerve damage. Topical CoQ10 + Vit E TPGS solution was applied to the rats in the treatment group, one drop twice a day for 3 weeks. On the other hand, physiological drops were applied to the experimental group 2 times a day for 3 weeks. After 3 weeks, the optic nerves of the rats were dissected and examined histopathologically. In electron microscopic examination of the treatment group, it was noted that the myelin sheath in the majority of myelinated nerve fibers and the normal structures of mitochondria, neurotubules, and neurofilaments in the axoplasm were preserved. It was observed that the oligodendrocytes surrounded the myelinated axons. In the experimental group, significant degenerative changes were observed in myelinated nerve fibers in many areas. The number of myelinated axons was significantly increased in the treatment group compared to the experimental group (p = .0028). In the light of the data obtained, the neuroprotective effect of the topically used CoQ10 + Vit E TPGS molecule was found to be histopathologically effective in our experimental study.

Topics: Animals; Disease Models, Animal; Male; Optic Neuropathy, Ischemic; Rats; Rats, Wistar; Ubiquinone; Vitamin E

Traumatic brain injury (TBI) is a major cause of disability and death. Mild TBI (mTBI) constitutes ~75% of all TBI cases. Repeated exposure to mTBI (rmTBI), leads to the exacerbation of the symptoms compared to single mTBI. To date, there is no FDA-approved drug for TBI or rmTBI. This research aims to investigate possible rmTBI neurotherapy by targeting TBI pathology-related mechanisms. Oxidative stress is partly responsible for TBI/rmTBI neuropathologic outcomes. Thus, targeting oxidative stress may ameliorate TBI/rmTBI consequences. In this study, we hypothesized that mitoquinone (MitoQ), a mitochondria-targeted antioxidant, would ameliorate TBI/rmTBI associated pathologic features by mitigating rmTBI-induced oxidative stress. To model rmTBI, C57BL/6 mice were subjected to three concussive head injuries. MitoQ (5 mg/kg) was administered intraperitoneally to rmTBI+MitoQ mice twice per week over one month. Behavioral and cognitive outcomes were assessed, 30 days following the first head injury, using a battery of behavioral tests. Immunofluorescence was used to assess neuroinflammation and neuronal integrity. Also, qRT-PCR was used to evaluate the expression levels of antioxidant enzymes. Our findings indicated that MitoQ alleviated fine motor function and learning impairments caused by rmTBI. Mechanistically, MitoQ reduced astrocytosis, microgliosis, dendritic and axonal shearing, and increased the expression of antioxidant enzymes. MitoQ administration following rmTBI may represent an efficient approach to ameliorate rmTBI neurological and cellular outcomes with no observable side effects.

Topics: Animals; Antioxidants; Brain Concussion; Brain Injuries, Traumatic; Dietary Supplements; Disease Models, Animal; Mice; Mice, Inbred C57BL; Organophosphorus Compounds; Oxidative Stress; Ubiquinone

Recent studies have demonstrated that airway basal stem cells (BCs) transplantation can ameliorate bleomycin-induced idiopathic pulmonary fibrosis (IPF) through lung regeneration promotion. However, BCs under oxidative stress in the alveolar microenvironment are poor in survival, causing unsatisfied efficacy of BCs transplantation. In this study, we investigated whether Coenzyme Q10(CoQ10) counteracts oxidative stress in the alveolar microenvironment, thus improved the efficacy of BCs transplantation for IPF treatment.. The protective effects of CoQ10 on H. CoQ10 blocked H

Topics: Animals; Apoptosis; Bleomycin; Cells, Cultured; Disease Models, Animal; Humans; Idiopathic Pulmonary Fibrosis; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Regeneration; Stem Cell Transplantation; Ubiquinone

Alzheimer's disease (AD) is a degenerative disease that causes memory and learning impairments as well as dementia. Coenzyme Q10 (CoQ10) is an anti-inflammatory and anti-oxidative stress supplement that can improve inflammation and oxidative stress associated with AD. This study investigated the effects of drug delivery of COQ10 by exosomes derived from adipose-derived stem cells (ADSCs-Exo) on cognition, memory, and neuronal proliferation in a rat model of Streptozotocin (STZ)-induced AD. Since the establishment of the AD model, the rats have received intraperitoneal injections of CoQ10, Exo, or CoQ10-loaded ADSCs-Exo (Exo+ CoQ10). The passive avoidance test and the Morris water maze (MWM) were used to assess memory and cognition changes. Cell density was determined using histological methods. The expression of BDNF was measured using an ELISA kit. SOX2 expression was determined using immunohistochemistry. According to the results of the MWM and passive avoidance task, Exo+CoQ10 significantly improved STZ-induced memory impairment compared to CoQ10 and Exo groups alone. Furthermore, BDNF expression increased in the STZ-induced rats after Exo+ CoQ10, when compared to the CoQ10 and Exo groups. In addition, Exo+CoQ10 had the highest cell density and SOX2 gene expression, when compared to the CoQ10 and Exo groups. According to the findings of this study, Exo+ COQ10 enhanced cognition and memory deficiency in Alzheimer's disease by boosting BDNF and SOX2 levels in the hippocampus. Hence, the use of exosomes derived from adipose-derived stem cells as the carrier of CoQ10 may increase the therapeutic effect of CoQ10, which can possibly be due to the regenerative properties of the exosomes.

Topics: Alzheimer Disease; Animals; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Exosomes; Neuroprotective Agents; Rats; Stem Cells; Streptozocin; Ubiquinone

Osteoarthritis (OA) is the most common degenerative joint disease and is characterized by breakdown of joint cartilage. Coenzyme Q10 (CoQ10) exerts diverse biological effects on bone and cartilage; observational studies have suggested that CoQ10 may slow OA progression and inflammation. However, any effect of CoQ10 on OA remains unclear. Here, we investigated the therapeutic utility of CoQ10-micelles.. Seven-week-old male Wistar rats were injected with monosodium iodoacetate (MIA) to induce OA. CoQ10-micelles were administered orally to MIA-induced OA rats; celecoxib served as the positive control. Pain, tissue destruction, and inflammation were measured. The expression levels of catabolic and inflammatory cell death markers were assayed in CoQ10-micelle-treated chondrocytes.. Oral supplementation with CoQ10-micelles attenuated OA symptoms remarkably, including pain, tissue destruction, and inflammation. The expression levels of the inflammatory cytokines IL-1β, IL-6, and MMP-13, and of the inflammatory cell death markers RIP1, RIP3, and pMLKL in synovial tissues were significantly reduced by CoQ10-micelle supplementation, suggesting that CoQ10-micelles might attenuate the synovitis of OA. CoQ10-micelle addition to cultured OA chondrocytes reduced the expression levels of catabolic and inflammatory cell death markers.. CoQ10-micelles might usefully treat OA.

Topics: Animals; Cartilage, Articular; Cell Death; Chondrocytes; Disease Models, Animal; Inflammation; Iodoacetic Acid; Male; Micelles; Nociceptive Pain; Osteoarthritis; Rats; Rats, Wistar; Ubiquinone

Topics: Animals; Disease Models, Animal; Encephalitis; HIV Infections; Mesylates; Mice; Organophosphorus Compounds; Ubiquinone

Sepsis is an uncontrolled systemic infection, withcomplex pathophysiology that may result in acute lung organ damage and cause multiple organ failure. Although much research has been conducted to illuminate sepsis's complex pathophysiology, sepsis treatment protocols are limited, and sepsis remains an important cause of mortality andmorbidity in intensive care units.Various studies have shown that idebenone (IDE) possesses strong antioxidant properties, which inhibit lipid peroxidation and protect cells from oxidative damage. The present study aimed to evaluate the protective effects of IDE against lung injury in a cecal ligation and puncture (CLP)-induced sepsis rat model.. Male albino Wistar rats were used. The animals were divided into a healthy control (no treatment), CLP, IDE control (200 mg/kg), and CLP + IDE subgroups (50 mg/kg, 100 mg/kg, and 200 mg/kg), with nine rats in each group.IDE was administered 1 h after CLP induction.To evaluate the protective effects of IDE, lung tissues were collected 16 h after sepsis for biochemical, immunohistochemical staining, and histopathological examination.. IDE significantly ameliorated sepsis-induced disturbances in oxidative stress-related factors, with its effects increasing in accordance with the dose.IDE also abolished histopathological changes in lung tissues associated with CLP.Furthermore, interleukin 1 beta (IL-1β)and tumor necrosis factor-alpha (TNF-α) immunopositivity markedly decreased in the septic rats following IDE treatment.. IDE largely mitigated the inflammatory response in sepsis-induced lung injury by decreasing free radicals and preventing lipid peroxidation. The results suggest that IDE may represent a potential novel therapeutic drug for sepsis treatment.

Topics: Animals; Disease Models, Animal; Lung; Male; Oxidative Stress; Rats; Rats, Wistar; Sepsis; Ubiquinone

The aim of this study was to investigate the effect of coenzyme Q10 (CoQ10), a commonly used nutritional supplement, on intracranial aneurysm (IA) initiation and progression in a mouse model, as well as the mechanism.. CoQ10 promoted the expression of nuclear factor erythroid 2-related factor 2 and antioxidant enzymes. In H. CoQ10 is effective in reducing oxidative stress in VSMCs, thereby attenuating IA formation and rupture in mice. CoQ10 also alleviates inflammation and restores normal phenotypes of VSMCs in the cerebral arteries. Our data suggest that CoQ10 is a potentially effective drug for managing IA.. To investigate the effect of CoQ10, a commonly used nutritional supplement, on IA initiation and progression in a mouse model, as well as the mechanism. CoQ10 promoted the expression of Nrf2 and antioxidant enzymes. In H

Topics: Animals; Antioxidants; Disease Models, Animal; Hydrogen Peroxide; Intracranial Aneurysm; Mice; Oxidative Stress; Ubiquinone

The Slc4a11 knock out (KO) mouse model recapitulates the human disease phenotype associated with congenital hereditary endothelial dystrophy (CHED). Increased mitochondrial reactive oxygen species (ROS) in the Slc4a11 KO mouse model is a major cause of edema and endothelial cell loss. Here, we asked if autophagy was activated by ROS in the KO mice.. Immortalized cell lines and mouse corneal endothelia were used to measure autophagy and lysosome associated protein expressions using Protein Simple Wes immunoassay. Autophagy and lysosome functions were examined in wild type (WT) and KO cells as well as animals treated with the mitochondrial ROS quencher MitoQ.. Even though autophagy activation was evident, autophagy flux was aberrant in Slc4a11 KO cells and corneal endothelium. Expression of lysosomal proteins and lysosomal mass were decreased along with reduced nuclear translocation of lysosomal master regulator, transcription factor EB (TFEB). MitoQ reversed aberrant lysosomal functions and TFEB nuclear localization in KO cells. MitoQ injections in KO animals reduced corneal edema and decreased the rate of endothelial cell loss.. Mitochondrial ROS disrupts TFEB signaling causing lysosomal dysfunction with impairment of autophagy in Slc4a11 KO corneal endothelium. Our study is the first to identify the presence as well as cause of lysosomal dysfunction in an animal model of CHED, and to identify a potential therapeutic approach.

Topics: Animals; Anion Transport Proteins; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blotting, Western; Cathepsin L; Cells, Cultured; Corneal Dystrophies, Hereditary; Disease Models, Animal; Endothelium, Corneal; Gene Expression Regulation; Immunohistochemistry; Injections, Intraperitoneal; Lysosomes; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Mitochondria; Organophosphorus Compounds; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Symporters; Transfection; Ubiquinone

To evaluate the efficacy of antioxidants in cellular-level post-ischemia/reperfusion injury of the testis and to validate these effects with. Fifty-six adult male rats were randomly divided into seven groups-Group 1: sham; Group 2: ischemia/reperfusion only group; Group 3: ischemia was induced and vitamin E (100 mg/kg) was administered intraperitoneally 30 min before reperfusion; Group 4: vitamin E was given intraperitoneally without ischemia/reperfusion; Group 5: ischemia was induced and coenzyme Q10 (10 mg/body weight) was administered intraperitoneally 30 min before reperfusion; Group 6: coenzyme Q10 was administered intraperitoneally without ischemia/reperfusion; Group 7: ischemia was induced and coenzyme Q10 + vitamin E was administered intraperitoneally 30 min before reperfusion. After detorsion, fluorodeoxyglucose was applied to all groups according to the animals' weight and fluorodeoxyglucose positron emission tomography was performed after 1 h. In pursuit of imaging, orchiectomy was performed for histopathological and biochemical evaluations.. A significant effect of group on catalase, maximum standardized uptake value, and seminiferous tubule diameters (p < 0.005) was observed. According to this, combining ischemia/reperfusion with vitamin E increased the maximum standardized uptake value significantly higher than in all other groups; in addition, catalase was significantly higher than in Groups 4-6. Histopathological outcomes revealed that "sham" had significantly larger seminiferous tubule diameter than Groups 2-4. Also, "ischemia/reperfusion" was the only group which had significantly smaller seminiferous tubule diameters than Groups 6 and 7.. In contrast to vitamin E, coenzyme Q10 provided remarkable regression of oxidative stress-induced enzymes and revealed consistent effects on histopathological outcomes, which were validated with fluorodeoxyglucose positron emission tomography imaging.

Topics: Animals; Disease Models, Animal; Fluorodeoxyglucose F18; Glucose; Male; Positron-Emission Tomography; Radiopharmaceuticals; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Testis; Ubiquinone; Vitamin E; Vitamins

Mitochondrial permeability transition pore (mPTP) closure triggers cardiomyocyte differentiation during development while pathological opening causes cell death during myocardial ischemia-reperfusion and heart failure. Ubiquinone modulates the mPTP; however, little is known about its mechanistic role in health and disease. We previously found excessive proton leak in newborn Fmr1 KO mouse forebrain caused by ubiquinone deficiency and increased open mPTP probability. Because of the physiological differences between the heart and brain during maturation, we hypothesized that developing Fmr1 KO cardiomyocyte mitochondria would demonstrate dissimilar features.. Newborn male Fmr1 KO mice and controls were assessed. Respiratory chain enzyme activity, ubiquinone content, proton leak, and oxygen consumption were measured in cardiomyocyte mitochondria. Cardiac function was evaluated via echocardiography.. In contrast to controls, Fmr1 KO cardiomyocyte mitochondria demonstrated increased ubiquinone content and decreased proton leak. Leak was cyclosporine (CsA)-sensitive in controls and CsA-insensitive in Fmr1 KOs. There was no difference in absolute mitochondrial respiration or cardiac function between strains.. These findings establish the newborn Fmr1 KO mouse as a novel model of excess ubiquinone and closed mPTP in the developing heart. Such a model may help provide insight into the biology of cardiac development and pathophysiology of neonatal heart failure.. Ubiquinone is in excess and the mPTP is closed in the developing FXS heart. Strengthens evidence of open mPTP probability in the normally developing postnatal murine heart and provides new evidence for premature closure of the mPTP in Fmr1 mutants. Establishes a novel model of excess CoQ and a closed pore in the developing heart. Such a model will be a valuable tool used to better understand the role of ubiquinone and the mPTP in the neonatal heart in health and disease.

Topics: Animals; Atractyloside; Cyclosporine; Disease Models, Animal; Electron Transport; Fetal Heart; Fragile X Mental Retardation Protein; Fragile X Syndrome; Guanosine Diphosphate; Male; Mice; Mice, Knockout; Mitochondria, Heart; Mitochondrial Permeability Transition Pore; Myocytes, Cardiac; Oxygen Consumption; Proton-Motive Force; Single-Blind Method; Ubiquinone

Cigarette smoking, which induces airway inflammation and mucus hypersecretion, is a major risk factor for the development of cigarette smoke (CS)-induced airway disorders. In this study, we investigated the effects and mechanisms of mitoquinone (MitoQ), a mitochondria-targeted antioxidant, on CS-induced airway inflammation and mucus hypersecretion in mice.. C57BL/6J mice were exposed to CS for 75 min twice daily, 5 days per week for 4 weeks. MitoQ (2.5, 5 mg/kg/day) was administered intraperitoneally 1 h before CS exposure. Bronchoalveolar lavage fluid (BALF) was obtained for cell counting and determination of pro-inflammatory cytokine levels. Lung tissue was collected for histological examination; Western blotting was used to measure levels of Mfn2, Drp1, cytochrome c, NF-κB p65, and IκBα.. Pretreatment with MitoQ significantly attenuated CS-induced thickening of the airway epithelium, peribronchial inflammatory cell infiltration, goblet cell hyperplasia and Muc5ac staining. The numbers of total cells, neutrophils and macrophages, as well as levels of TNF-α and IL-6 in BALF were remarkably decreased by MitoQ in a dose-dependent manner. MitoQ attenuated oxidative stress by preventing the CS-induced increase in malondialdehyde level and decrease in superoxide dismutase activity and GSH/GSSG ratio. MitoQ decreased the expression of mitochondrial fission protein Drp1 and increased that of mitochondrial fusion protein Mfn2, as well as reduced cytochrome c release into the cytosol. Furthermore, MitoQ suppressed IκBα degradation and NF-κB p65 nuclear translocation.. MitoQ attenuates inflammation, mucus hypersecretion, and oxidative stress induced by CS. It may exert these effects in part by modulating mitochondrial function and the NF-κB signal pathway.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytokines; Disease Models, Animal; Inflammation Mediators; Lung; Male; Mice, Inbred C57BL; Mitochondria; Mucus; NF-kappa B; Organophosphorus Compounds; Oxidative Stress; Pneumonia; Secretory Pathway; Signal Transduction; Smoke; Tobacco Products; Ubiquinone

Multiple Sclerosis (MS) is a chronic, progressive demyelinating disease of the central nervous system that causes the most disability in young people, besides trauma. Coenzyme Q10 (CoQ10)-also known as ubiquinone-is an endogenous lipid-soluble antioxidant in the mitochondrial oxidative respiratory chain which can reduce oxidative stress and inflammation, the processes associated with demyelination in MS. Cuprizone (CPZ) intoxication is a well-established model of inducing MS, best for studying demyelination-remyelination. In this study, we examined for the first time the role of CoQ10 in preventing demyelination and induction of remyelination in the chronic CPZ model of MS. 40 male mice were divided into four groups. 3 group chewed CPZ-containing food for 12 weeks to induce MS. After 4 weeks, one group were treated with CoQ10 (150 mg/kg/day) by daily gavage until the end of the experiment, while CPZ poisoning continued. At the end of 12 weeks, tail suspension test (TST) and open field test (OFT) was taken and animals were sacrificed to assess myelin basic protein (MBP), oligodendrocyte transcription factor-1 (Olig1), tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) by real-time polymerase chain reaction (real-time PCR) and total antioxidant capacity (TAC) and superoxide dismutase (SOD) by Elisa test. Luxol fast blue (LFB) staining was used to evaluate histological changes. CoQ10 administration promoted remyelination in histological findings. MBP and Olig-1 expression were increased significantly in CoQ10 treated group compare to the CPZ-intoxicated group. CoQ10 treatment alleviated stress oxidative status induced by CPZ and dramatically suppress inflammatory biomarkers. CPZ ingestion made no significant difference between normal control group and the CPZ-intoxicated group in TST and OFT. CoQ10 can enhance remyelination in the CPZ model and potentially might have same effects in MS patients.

Topics: Animals; Behavior, Animal; Biomarkers; Chronic Disease; Corpus Callosum; Cuprizone; Cytokines; Demyelinating Diseases; Disease Models, Animal; Inflammation; Inflammation Mediators; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Oxidative Stress; Remyelination; Ubiquinone

Radiation enteropathy is one the most common clinical issue for patients receiving radiotherapy for abdominal/pelvic tumors which severely affect the quality of life of cancer patients due to dysplastic lesions (ischemia, ulcer, or fibrosis) that aggravate the radiation damage. Herein, this study demonstrated the prophylactic role of coenzyme Q10 (CoQ10), a powerful antioxidant, against radiotherapy-induced gastrointestinal injury. Male Sprague Dawley rats were divided into four groups: group 1 was defined as control, and group 2 was the irradiated group. Group 3 and 4 were CoQ10 control and radiation plus CoQ10 groups, respectively. CoQ10 (10 mg/kg) was orally administered for 10 days before 10 Gy whole-body radiation and was continued for 4 days post-irradiation. CoQ10 administration protected rats delivered a lethal dose of ϒ-radiation from changes in crypt-villus structures and promoted regeneration of the intestinal epithelium. CoQ10 attenuated radiation-induced oxidative stress by decreasing lipid peroxidation and increasing the antioxidant enzyme catalase activity and reduced glutathione level. CoQ10 also counteracts inflammatory response mediated after radiation exposure through downregulating intestinal NF-ĸB expression which subsequently decreased the level of inflammatory cytokine IL-6 and the expression of COX-2. Radiation-induced intestinal fibrosis confirmed via Masson's trichrome staining occurred through upregulating transforming growth factor (TGF)-β1 and matrix metalloproteinase (MMP)-9 expression, while CoQ10 administration significantly diminishes these effects which further confirmed the anti-fibrotic property of CoQ10. Therefore, CoQ10 is a promising radioprotector that could prevent intestinal complications and enhance the therapeutic ratio of radiotherapy in patients with pelvic tumors through suppressing the NF-kB/TGF-β1/MMP-9 signaling pathway.

Topics: Animals; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Inflammation; Intestinal Diseases; Male; Matrix Metalloproteinase 9; NF-kappa B; Radiation Injuries; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Ubiquinone; Vitamins

The increase in some factors following cerebral ischemia, especially Matrix metalloproteinase (MMPs) and inflammatory factors lead to blood-brain barrier (BBB) damages, edema and neuronal death. Previous studies have shown that these molecules are miRNA-149-5p (miR-149) and Coenzyme (Co) Q10 targets. Therefore, in this study, the effect of mimic of miRNA-149-5p (mimic miR) and CoQ10 on the expression of metalloproteinase 1 and 2 and inflammatory cytokines following injury caused by cerebral ischemia is investigated. Cerebral ischemia was modeled by Middle Cerebral Artery Occlusion (MCAO). Male Wistar rats were randomly divided into 6 groups: sham (without surgery and treatment), control (MCAO), negative control (NC): MCAO + scrambled miR, vehicle: MCAO + Ethanole, first treatment: MCAO + mimic miR, second treatment: MCAO + Q10. Each group was divided into 6 subgroups to evaluate neurological defects, the volume of tissue damage using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, blood-brain barrier permeability using cerebral Evans Blue (EB) staining, edema by measuring the percentage of brain water, MMP-2,9 mRNA and miR-149-5p levels using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and the levels of IL-6 and TNF-α proteins using ELISA. The data obtained from this study showed that the use of mimic miR and Q10 increased the level of miR-149, decreased the extent of neurological defects and tissue damage, increased BBB integrity, decreased brain water percentage and also decreased the level of inflammatory cytokines and MMPs. It seems that the use mimic of miRNA-149-5p and Q10 can have a protective effect on the brain by reducing MMPs and inflammatory factors following cerebral ischemia and this could lead to a new treatment strategy to reduce the complications of cerebral ischemia.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Brain Ischemia; Cytokines; Disease Models, Animal; Male; Metalloproteases; MicroRNAs; Neuroprotective Agents; Rats; Rats, Wistar; Ubiquinone

Methotrexate (MTX) has toxic effects on the uterus and ovaries via oxidative stress. Coenzyme Q10 (CoQ10) is an important component in electron transport in the mitochondria and an antioxidant in cellular metabolism through the inhibition of lipid peroxidation. The aim of this study was to investigate the preventive effects of CoQ10 on MTX-induced utero-ovarian damage and oxidative stress in rats.In this experimental study, 30 albino Wistar female rats were divided randomly into three groups. Once a day for a month, 10 mg/kg of CoQ10 was orally administered to the rats in the MTX+CoQ10 group, while the same volume of olive oil was administered orally to the other two groups. One hour thereafter, 20 mg/kg of MTX was injected intraperitoneally into the rats in the MTX and MTX+CoQ10 groups; the remaining group was the control. At the end of the month, biochemical and histopathologic examinations were performed on the extracted uteri and ovaries. In the uterine ovarian tissues of the animals in the MTX group, there was an increase in oxidative stress mediators and a decrease in antioxidant and anti-inflammatory mediators, but these trends were reversed in the MTX+CoQ10 group, demonstrating the antioxidant effects of CoQ10. MTX leads to oxidative stress-related ovarian and uterine injury, and CoQ10 may be useful for protecting ovarian and uterine tissue from such injury.

Topics: Animals; Antioxidants; Disease Models, Animal; Female; Humans; Male; Methotrexate; Ovarian Diseases; Oxidative Stress; Protective Agents; Rats; Ubiquinone; Uterine Diseases

Several studies have shown that coenzyme Q10 (CoQ10) can rescue ovarian aging and that ovarian surface epithelium (OSE)-derived ovarian stem cells (OSCs) are useful for treating infertility due to ovarian aging. However, few studies have examined the effect of CoQ10 on OSCs. This study was aimed to investigate whether CoQ10 activates OSCs and recovers ovarian function in a 4-vinylcyclohexene diepoxide (VCD)-induced mouse model of ovarian failure.. Forty female C57BL/6 mice aged 6 weeks were randomly divided into four groups (n = 10/group): a control group administered saline orally, a CoQ10 group administered 150 mg/kg/day of CoQ10 orally in 1 mL of saline daily for 14 days, a VCD group administered 160 mg/kg/day of VCD i.p. in 2.5 mL of saline/kg for 5 days, and a VCD + CoQ10 group administered VCD i.p. for 5 days injection and CoQ10 (150 mg/kg/day) orally for 14 days. After treatment, follicle counts were evaluated by hematoxylin and eosin (H&E) staining, and ovarian mRNA expressions of Bmp-15, Gdf-9, and c-Kit were examined by quantitative real-time PCR. Serum FSH, AMH, and ROS levels were also measured. Oocyte-like structure counts and the expressions of Oct-4 and MVH were also evaluated after culturing OSE for 3 weeks. In a second experiment, 32 female mice were administered CoQ10 as described above, induced to superovulate using PMSG and hCG, and mated. Numbers of zygotes and embryo development rate were examined.. Postcultured OSE showed significant increases in the numbers of oocyte-like structure and that the expression of Oct-4 and MVH were higher in the VCD + CoQ10 group than in the VCD group (p < 0.05). Numbers of surviving follicles from primordial to antral follicles, numbers of zygotes retrieved and embryo development rate to blastocyst were significantly greater in the VCD + CoQ10 group than in the VCD group (p < 0.01). Serum AMH level and ovarian expressions of Bmp-15, Gdf-9 and c-Kit were also significantly greater in the VCD + CoQ10 group than in the VCD group (p < 0.05). In contrast, serum ROS level was significantly lower in the VCD + CoQ10 group than in the VCD group (p < 0.05).. This study shows that CoQ10 stimulates the differentiation of OSE-derived OSCs and confirms that CoQ10 can reduce ROS levels and improve ovarian function and oocyte quality in mice with VCD-induced ovarian failure.

Topics: Animals; Cells, Cultured; Cyclohexenes; Disease Models, Animal; Epithelium; Female; In Vitro Oocyte Maturation Techniques; Mice; Mice, Inbred C57BL; Oocytes; Ovarian Diseases; Ovary; Stem Cells; Ubiquinone; Vinyl Compounds

Ischaemia-reperfusion (IR) injury makes a major contribution to graft damage during kidney transplantation. Oxidative damage to mitochondria is an early event in IR injury. Therefore, the uptake, safety, and efficacy of the mitochondria-targeted antioxidant MitoQ were investigated in models of transplant IR injury.. MitoQ uptake by warm and cooled pairs of pig and declined human kidneys was measured when preserved in cold static storage or by hypothermic machine perfusion. Pairs of pigs' kidneys were exposed to defined periods of warm and cold ischaemia, flushed and stored at 4°C with or without MitoQ (50 nmol/l to 250 µmol/l), followed by reperfusion with oxygenated autologous blood in an ex vivo normothermic perfusion (EVNP). Pairs of declined human kidneys were flushed and stored with or without MitoQ (5-100 µmol/l) at 4°C for 6 h and underwent EVNP with ABO group-matched blood.. Stable and concentration-dependent uptake of MitoQ was demonstrated for up to 24 h in pig and human kidneys. Total blood flow and urine output were significantly greater in pig kidneys treated with 50 µmol/l MitoQ compared with controls (P = 0.006 and P = 0.007 respectively). In proof-of-concept experiments, blood flow after 1 h of EVNP was significantly greater in human kidneys treated with 50 µmol/l MitoQ than in controls (P ≤ 0.001). Total urine output was numerically higher in the 50-µmol/l MitoQ group compared with the control, but the difference did not reach statistical significance (P = 0.054).. Mitochondria-targeted antioxidant MitoQ can be administered to ischaemic kidneys simply and effectively during cold storage, and may improve outcomes after transplantation.

Topics: Animals; Antioxidants; Disease Models, Animal; Humans; Kidney; Kidney Transplantation; Organ Preservation; Organophosphorus Compounds; Reperfusion Injury; Swine; Ubiquinone

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Congresses as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Repositioning; Dysbiosis; Gastrointestinal Microbiome; Gene Expression Regulation; Humans; Lupus Erythematosus, Systemic; Metformin; Mice; RNA-Seq; Single-Cell Analysis; Ubiquinone; Videoconferencing

Idebenone (IDB) has demonstrated the potential to treat mitochondrial and neurodegenerative diseases, including Alzheimer's disease (AD). However, its therapeutic effects are compromised by poor compliance due to low bioavailability. The objective of this study is to fabricate IDB nanorods (IDBNRs) to improve oral bioavailability and increase concentrations in the brain in order to enhance therapeutic effects of IDB in the treatment of AD. IDBNRs showed desired sizes and rod-shaped morphologies. The release rate and the antioxidant activity of IDBNRs were improved relative to other delivery routes. The plasma and brain concentrations were enhanced due to rapid release into the systemic circulation. In behavioral tests, mice treated orally with IDBNRs showed amelioration of AD-induced impairment of learning and memory. Thus, because of improved efficiency of drug delivery, doses can be reduced, and the compliance and therapeutic experience of patients can be improved. IDBNRs may provide effective and convenient treatments for AD patients in the future.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Nanotubes; Neuroprotective Agents; Ubiquinone

Muscle mass is important for health. Decreased testicular androgen production (hypogonadism) contributes to the loss of muscle mass, with loss of limb muscle being particularly debilitating. Androgen replacement is the only pharmacological treatment, which may not be feasible for everyone. Prior work showed that markers of reactive oxygen species and markers of mitochondrial degradation pathways were higher in the limb muscle following castration. Therefore, we tested whether an antioxidant preserved limb muscle mass in male mice subjected to a castration surgery. Subsets of castrated mice were treated with resveratrol (a general antioxidant) or MitoQ (a mitochondria targeted antioxidant). Relative to the non-castrated control mice, lean mass, limb muscle mass, and grip strength were partially preserved only in castrated mice treated with MitoQ. Independent of treatment, markers of mitochondrial degradation pathways remained elevated in all castrated mice. Therefore, a mitochondrial targeted antioxidant may partially preserve limb muscle mass in response to hypogonadism.

Topics: Animals; Antioxidants; Disease Models, Animal; Drug Delivery Systems; Hand Strength; Hypogonadism; Male; Mice; Mitochondria; Mitochondria, Muscle; Muscle, Skeletal; Orchiectomy; Organophosphorus Compounds; Resveratrol; Ubiquinone

In this study, it was aimed to investigate the effect of coenzyme Q10 (CoQ10) on cisplatin-induced oxidative retinal damage in rats biochemically and histopathologically.. Thirty male Wistar albino rats were divided into 3 groups randomly: untreated control (C group), only 2.5 mg/kg cisplatin daily administrated group for 2 weeks (CP group), 2.5 mg/kg cisplatin + 20 mg/kg orally CoQ10 daily administrated group for 2 weeks (CoQC group). At the end of experimental period, blood samples obtained before sacrification for the biochemical examination of serum malondialdehyde (MDA), total glutathione (tGSH), total oxidant system (TOS), total antioxidant systemic (TAS) levels and after eyes were removed for examined histopathology.. As a result of our study, severe histopathological damage was detected in the retinal tissue of the cisplatin group with serum malondialdehyde (MDA) and total oxidant system (TOS) levels were high and total glutathione (tGSH) and total antioxidant systemic (TAS) levels were low. However, it was observed that the histopathological damage associated with cisplatin was decreased in the retinal tissue of the CoQ10 group, which inhibited the increase in blood serum MDA/TOS levels and decrease in tGSH/TAS levels.. The biochemical and histopathological results of our study were compatible with each other, so we concluded that the damage to the rat retinal tissue caused by cisplatin may be reversible with coenzyme.

Topics: Administration, Oral; Animals; Antioxidants; Cisplatin; Disease Models, Animal; Humans; Male; Oxidative Stress; Rats; Retina; Retinal Diseases; Ubiquinone

Doxorubicin (DOX) is used as an anticancer drug despite its several side effects, especially its irreversible impacts on cardiotoxicity. Coenzyme Q10 (Q10) as a powerful antioxidant and lisinopril (LIS) as an angiotensin-converting enzyme inhibitor seem to provide protection against DOX-induced cardiotoxicity. Therefore, this study aimed to assess the cardioprotective effects of Q10 and LIS against DOX-induced cardiotoxicity in rats. Adult male Sprague-Dawley rats were randomly assigned into the control, LIS, Q10, DOX, DOX + LIS, and DOX + Q10 groups. On day 21, ECG was recorded and the right ventricle was dissected for evaluation of catalase activity and malondialdehyde (MDA) concentration. Additionally, the left ventricle and the sinoatrial (SA) node were dissected to assess the stereological parameters. The results of ECG indicated bradycardia and increase in QRS duration and QT interval in the DOX group compared to the control group. Meanwhile, the total volumes of the left ventricle, myocytes, and microvessels and the number of cardiomyocyte nuclei decreased, whereas the total volume of the connective tissue and the mean volume of cardiomyocytes increased in the DOX group. On the other hand, the SA node and the connective tissue were enlarged, while the volume of the SA node nuclei was reduced in the DOX group. Besides, catalase activity was lower and MDA concentration was higher in the DOX-treated group. Q10 could recover most stereological parameters, catalase activity, and MDA concentration. LIS also prevented some stereological parameters and ECG changes and improved catalase activity and MDA concentration in the DOX group. The findings suggested that Q10 and LIS exerted cardioprotective effects against DOX-induced cardiac toxicity.

Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Catalase; Disease Models, Animal; Doxorubicin; Electrocardiography; Heart Conduction System; Heart Diseases; Heart Rate; Lisinopril; Male; Malondialdehyde; Myocytes, Cardiac; Rats, Sprague-Dawley; Ubiquinone

Parkinson's disease (PD) is a complex neurodegenerative disease in which the understanding of the underlying molecular mechanisms can be constructive in the diagnosis and treatment. Matrix metalloproteinase (MMPs) elevation and damage to the blood-brain barrier (BBB) are critical mechanisms involved in the PD separation. Studies have revealed that changes in miR-149-5p and CoQ10 are associated with BBB damage, and CoQ10 can affect the levels of some miRs. Hence, in the present study, we aimed to evaluate CoQ10 and miR-149-5p mimic on miR-149-5p, MMPs and TH expression, and behavioral functions of the PD models. PD was induced by injection of 6-OHDA into the rats' Medial Forbrain Bundle (MFB). The behavioral tests, including the Rotation test, Rotarod test, and Open field test, have been directed two weeks after PD induction. Next, the MiR-149-5p mimic (miR-mimic) and CoQ10 have been administered to rats. The same behavioral tests have been evaluated two weeks after administration to investigate the effect of miR-149-5p mimic and CoQ10. The rats were followed extra four weeks, and the behavioral tests have performed again. Finally, the expression of MMPs and miR-149-5p genes was measured using RT-qPCR, and tyrosine hydroxylase (TH) was assessed through immunohistochemistry analysis. According to the obtained results, the level of miR-149-5p has decreased, followed by PD induction in rats. RT-qPCR analysis has represented upregulation and downregulation of miR-149-5p and MMP-2,9, respectively, after miR-mimic and CoQ10 treatment. The treated rats have also represented improved motor function and increased TH +  cells in the striatum according to the behavioral tests and immunohistochemistry assay. Taking together miR-149 and CoQ10 has shown to have an impressive potential to prevent damage to dopaminergic neurons caused by 6-OHDA injection through reducing MMP-2,9, increased TH expression, and improved motor function.

Topics: Animals; Disease Models, Animal; Matrix Metalloproteinases; MicroRNAs; Neurodegenerative Diseases; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Rats; Ubiquinone

Shc expression rises in human nonalcoholic steatohepatitis (NASH) livers, and Shc-deficient mice are protected from NASH-thus Shc inhibition could be a novel therapeutic strategy for NASH. Idebenone was recently identified as the first small-molecule Shc inhibitor drug. We tested idebenone in the fibrotic methionine-choline deficient (MCD) diet and the metabolic fast food diet (FFD) mouse models of NASH. In the fibrotic MCD NASH model, idebenone reduced Shc expression and phosphorylation in peripheral blood mononuclear cells and Shc expression in the liver; decreased serum alanine aminotransferase and aspartate aminotransferase; and attenuated liver fibrosis as observed by quantitative polymerase chain reaction (qPCR) and hydroxyproline quantification. In the metabolic FFD model, idebenone administration improved insulin resistance, and reduced inflammation and fibrosis shown with qPCR, hydroxyproline measurement, and histology. Thus, idebenone ameliorates NASH in two mouse models. As an approved drug with a benign safety profile, Idebenone could be a reasonable human NASH therapy.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Choline Deficiency; Diet; Disease Models, Animal; Fast Foods; Leukocytes, Mononuclear; Liver; Liver Cirrhosis; Male; Methionine; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phosphorylation; Protective Agents; Shc Signaling Adaptor Proteins; Signal Transduction; Therapeutics; Ubiquinone

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Autophagy; Autophagy-Related Proteins; Butanes; Cell Extracts; Cell Wall; Coronary Vessels; Disease Models, Animal; DNA Glycosylases; Hypoglycemic Agents; Lacticaseibacillus casei; Male; Metformin; Mice; Mitophagy; Mucocutaneous Lymph Node Syndrome; Myocardium; NLR Family, Pyrin Domain-Containing 3 Protein; Organophosphorus Compounds; Pyridinium Compounds; Reactive Oxygen Species; Ubiquinone; Ubiquitin-Protein Ligases

Leber's hereditary optic neuropathy (LHON) is a rare inherited blindness caused by mutations in the mitochondrial DNA (mtDNA). The disorder is untreatable and tricky, as the existing chemotherapeutic agent Idebenone alleviates symptoms rather than overcoming the underlying cause. Although some studies have made progress on allotopic expression for LHON, in situ mitochondrial gene therapy remains challenging, which may simplify delivery procedures to be a promising therapeutic for LHON. LHON becomes more difficult to manage in the changed mitochondrial microenvironment, including increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP). Herein, a pathologically responsive mitochondrial gene delivery vector named [triphenylphosphine-terminated poly(sulfur-containing thioketal undecafluorohexylamine histamine) and Ide-terminated poly(sulfur-containing thioketal undecafluorohexylamine histamine)] (TISUH) is reported to facilitate commendable in situ mitochondrial gene therapy for LHON. TISUH directly targets diseased mitochondria via triphenylphosphine and fluorination addressing the decreasing MMP. In addition, TISUH can be disassembled by high mitochondrial ROS levels to release functional genes for enhancing gene transfection efficiency and fundamentally correcting genetic abnormalities. In both traditional and gene-mutation-induced LHON mouse models, TISUH-mediated gene therapy shows satisfactory curative effect through the sustained therapeutic protein expression in vivo. This work proposes a novel pathologically responsive in situ mitochondrial delivery platform and provides a promising approach for refractory LHON as well as other mtDNA mutated diseases treatments.

Topics: Animals; Disease Models, Animal; DNA; DNA, Mitochondrial; Electron Transport Complex I; Fluorescent Dyes; Genetic Therapy; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mitochondria; Optic Atrophy, Hereditary, Leber; Polymers; Protein Subunits; Reactive Oxygen Species; Ubiquinone

In the present study, we investigated the cardioprotective effects of coenzyme Q10 (Q10) against doxorubicin (DOXO) induced cardiomyopathy. Twenty adult rats were distributed in four experimental groups: group 1 received NaCl 0.9% at 1 ml/day for 14 days; group 2 received Q10 at 1 mg/kg/day for 14 days; group 3 received initial 7 days of treatment with NaCl 0.9% followed by a single dose of doxorubicin (12.5 mg/kg IP) and another 7 days of NaCl; and group 4 received initial 7 days of Q10 1 mg/kg/day, followed by a single dose of doxorubicin (12.5 mg/kg IP) and another 7 days of Q10. At the end of 14 days, systolic, diastolic and mean blood pressure, electrocardiogram (ECG), complete blood count, and serum biochemical profile were evaluated. We also analyzed heart histological and ultrastructure analysis, and estimated heart's oxidative stress and lipid peroxidation. DOXO administration altered ECG, with increase heart rate, P-wave duration, PR interval duration, and T-wave amplitude. All the parameters were significantly reduced following Q10 treatment. DOXO also caused increase in CK, CK-MB, LDH, and urea levels, which were not mitigated by Q10 treatment. However, Q10 reduced oxidative stress by interfering with superoxide dismutase, significantly decreasing lipid peroxidation in heart tissue. DOXO administration also leads to several histological and ultrastructure alterations including cardiomyocyte degeneration and intense intracelullar autophagosomes, all minimized by Q10 treatment. Q10 treatment prevented the ECG changes, minimized oxidative stress, lipid peroxidation, and DOXO-induced heart tissue alterations. Our findings suggest that pre- and post-treatment with Q10 exerts potential cardioprotective effect against the DOX-induced cardiotoxicity.

Topics: Animals; Antioxidants; Cardiomyopathies; Cardiotoxicity; Disease Models, Animal; Doxorubicin; Lipid Peroxidation; Myocytes, Cardiac; Oxidative Stress; Rats, Wistar; Ubiquinone

A role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematosus (SLE). Idebenone is a coenzyme Q10 synthetic quinone analog and an antioxidant that has been used in humans to treat diverse diseases in which mitochondrial function is impaired. This study was undertaken to assess whether idebenone ameliorates lupus in murine models.. Idebenone was administered orally to MRL/lpr mice at 2 different doses (1 gm/kg or 1.5 gm/kg idebenone-containing diet) for 8 weeks. At peak disease activity, clinical, immunologic, and metabolic parameters were analyzed and compared to those in untreated mice (n = 10 per treatment group). Results were confirmed in the lupus-prone NZM2328 mouse model.. In MRL/lpr mice, idebenone-treated mice showed a significant reduction in mortality incidence (P < 0.01 versus untreated mice), and the treatment attenuated several disease features, including glomerular inflammation and fibrosis (each P < 0.05 versus untreated mice), and improved renal function in association with decreased renal expression of interleukin-17A (IL-17A) and mature IL-18. Levels of splenic proinflammatory cytokines and inflammasome-related genes were significantly decreased (at least P < 0.05 and some with higher significance) in mice treated with idebenone, while no obvious drug toxicity was observed. Idebenone inhibited neutrophil extracellular trap formation in neutrophils from lupus-prone mice (P < 0.05) and human patients with SLE. Idebenone also improved mitochondrial metabolism (30% increase in basal respiration and ATP production), reduced the extent of heart lipid peroxidation (by one-half that of untreated mice), and significantly improved endothelium-dependent vasorelaxation (P < 0.001). NZM2328 mice exposed to idebenone also displayed improvements in renal and systemic inflammation, reducing the kidney pathology score (P < 0.05), IgG/C3 deposition (P < 0.05), and the gene expression of interferon, proinflammatory, and inflammasome-related genes (at least P < 0.05 and some with higher significance).. Idebenone ameliorates murine lupus disease activity and the severity of organ damage, supporting the hypothesis that agents that modulate mitochondrial biologic processes may have a therapeutic role in human SLE.

Topics: Animals; Antioxidants; Disease Models, Animal; Extracellular Traps; Inflammation; Interleukin-17; Interleukin-18; Kidney; Lupus Erythematosus, Systemic; Mice; Mice, Inbred MRL lpr; Mitochondria; Ubiquinone

Topics: Animals; Cardenolides; Disease Models, Animal; Female; Fish Proteins; Gene Expression; Locomotion; Male; Mitochondria; Neuroprotective Agents; Organophosphorus Compounds; Parkinson Disease; Parkinsonian Disorders; Rotenone; Synucleins; Ubiquinone; Zebrafish

Oxidative stress is a key player of the inflammatory cascade responsible for the initiation of ulcerative colitis (UC). Although the short chain quinone idebenone is considered a potent antioxidant and a mitochondrial electron donor, emerging evidence suggests that idebenone also displays anti-inflammatory activity. This study evaluated the impact of idebenone in the widely used dextran sodium sulphate (DSS)-induced mouse model of acute colitis. Acute colitis was induced in C57BL/6J mice via continuous exposure to 2.5% DSS over 7 days. Idebenone was co-administered orally at a dose of 200 mg/kg body weight. Idebenone significantly prevented body weight loss and improved the disease activity index (DAI), colon length, and histopathological score. Consistent with its reported antioxidant function, idebenone significantly reduced the colonic levels of malondialdehyde (MDA) and nitric oxide (NO), and increased the expression of the redox factor NAD(P)H (nicotinamide adenine dinucleotide phosphate) dehydrogenase quinone-1 (NQO-1) in DSS-exposed mice. Immunohistochemistry revealed a significantly increased expression of tight junction proteins, which protect and maintain paracellular intestinal permeability. In support of an anti-inflammatory activity, idebenone significantly attenuated the elevated levels of pro-inflammatory cytokines in colon tissue. These results suggest that idebenone could represent a promising therapeutic strategy to interfere with disease pathology in UC by simultaneously inducing antioxidative and anti-inflammatory pathways.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Malondialdehyde; Mice; Mice, Inbred C57BL; NAD(P)H Dehydrogenase (Quinone); Nitric Oxide; Ubiquinone; Weight Loss

Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day

Topics: Animals; Antioxidants; Disease Models, Animal; Heart Failure; Mice; Mitochondria; Mitochondrial Dynamics; Myocardium; Myocytes, Cardiac; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; RNA, Untranslated; Ubiquinone

The impact of the mitochondria-targeted antioxidant MitoQ was evaluated in the cardiac alterations associated with obesity. Male Wistar rats were fed either a high fat diet (HFD, 35% fat) or a standard diet (CT, 3.5% fat) for 7 weeks and treated with MitoQ (200 µM). The effect of MitoQ (5 nM) in rat cardiac myoblasts treated for 24 h with palmitic acid (PA, 200 µM) was evaluated. MitoQ reduced cardiac oxidative stress and prevented the development of cardiac fibrosis, hypertrophy, myocardial

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Humans; Male; Mitochondria; Myocardium; Obesity; Organophosphorus Compounds; Oxidative Stress; Rats; Rats, Wistar; Ubiquinone

Cornelian cherries (CCs) belong to promising anti-obesity substances. We aimed to study effects of coenzyme Q10 (CoQ10) and two varieties of CCs on lipid profile, ROS, and nitric oxide (NO) production in obese rats. Male Zucker rats were divided into the control group and groups treated with CoQ10 (30mg/kg/day), or CC varieties: Koralovij Marka (KM) and Wild Type (WT) (5 g/kg/day,

Topics: Animals; Blood Pressure; Cornus; Disease Models, Animal; Lipid Metabolism; Lipids; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Organ Size; Oxidative Stress; Plant Extracts; Rats; Rats, Zucker; Reactive Oxygen Species; Ubiquinone

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Hypoglycemic Agents; Male; Mitochondria; Obesity; Organophosphorus Compounds; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Streptozocin; Ubiquinone

Recent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants.. Lupus-prone MRL-. MitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody .. These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.

Topics: Animals; Autoantibodies; Disease Models, Animal; Extracellular Traps; Female; Humans; Interferon Type I; Kidney; Kidney Diseases; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred MRL lpr; Mitochondria; Neutrophils; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; T-Lymphocytes; Ubiquinone

Neonatal ischemic stroke has a higher incidence than childhood stroke. Seizures are the first sign for the need for clinical assessment in neonates, but many questions remain regarding treatments and follow-up modalities. In the absence of a known pathophysiological mechanism, only supportive care is currently provided. Stroke-induced microglia activation and neuroinflammation are believed to play a central role in the pathological progression of neonatal ischemic stroke. We induced a photothrombotic infarction with Rose Bengal in neonatal rats to investigate the effects of pre- and post-treatment with Aspirin (ASA), Clopidogrel (Clop), and Coenzyme Q10 (CoQ10), which are known for their neuroprotective effects in adult stroke. Pre-stroke medication ameliorates cerebral ischemic injury and reduces infarct volume by reducing microglia activation, cellular reactive oxygen species (ROS) production, and cytokine release. Post-stroke administration of ASA, Clop, and CoQ10 increased motor function and reduced the volume of infarction, and the statistical evidence was stronger than that seen in the pre-stroke treatment. In this study, we demonstrated that ASA, Clop, and CoQ10 treatment before and after the stroke reduced the scope of stroke lesions and increased behavioral activity. It suggests that ASA, Clop, and CoQ10 medication could significantly have neuroprotective effects in the neonates who have suffered strokes.

Topics: Animals; Animals, Newborn; Aspirin; Brain Ischemia; Clopidogrel; Disease Models, Animal; Inflammation; Neuroprotective Agents; Rats; Rose Bengal; Stroke; Ubiquinone

To characterize the nanoparticle of antroquinonol from. The nano-SAC size was 37.68±5.91 nm, the zeta potential was 4.13±0.49 mV, encapsulation efficiency was 79.29±0.77%, and loading capacity was 32.45±0.02%. The nano-SAC can improve diabetes-induced reproductive dysfunction by regulating glucose, insulin, and oxidative enzyme and by increasing the level of testosterone, follicle-stimulating hormone, luteinizing hormone, and sperm count as well as sperm mobility. In testicular histopathology, the seminiferous tubules of. The nanoparticle of antroquinonol from

Topics: Animals; Antrodia; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Fasting; Glutathione Peroxidase; Humans; Insulin; Kidney; Liver; Male; Malondialdehyde; Nanoparticles; Oxidative Stress; Rats, Sprague-Dawley; Reproduction; Sperm Count; Sperm Motility; Streptozocin; Superoxide Dismutase; Testis; Ubiquinone

Fibromyalgia (FM) is one of the most common musculoskeletal pain conditions. Although the aetiology of FM is still unknown, mitochondrial dysfunction and the overproduction of reactive oxygen intermediates (ROI) are common characteristics in its pathogenesis. The reserpine experimental model can induce FM-related symptoms in rodents by depleting biogenic amines. However, it is unclear whether reserpine causes other pathophysiologic characteristics of FM. So far, no one has investigated the relevance of mitochondrial dysfunction in the reserpine-induced experimental FM model using protection- and insult-based mitochondrial modulators. Reserpine (1 mg/kg) was subcutaneously injected once daily for three consecutive days in male Swiss mice. We carried out analyses of reserpine-induced FM-related symptoms, and their modulation by using mitochondrial insult on ATP synthesis (oligomycin; 1 mg/kg, intraperitoneally) or mitochondrial protection (coenzyme Q10; 150 mg/kg/5 days, orally). We also evaluated the effect of reserpine on mitochondrial function using high-resolution respirometry and oxidative status. Reserpine caused nociception, loss in muscle strength, and anxiety- and depressive-like behaviours in mice that were consistent with clinical symptoms of FM, without inducing body weight and temperature alterations or motor impairment. Reserpine-induced FM-related symptoms were increased by oligomycin and reduced by coenzyme Q10 treatment. Reserpine caused mitochondrial dysfunction by negatively modulating the electron transport system and mitochondrial respiration (ATP synthesis) mainly in oxidative muscles and the spinal cord. These results support the role of mitochondria in mediating oxidative stress and FM symptoms in this model. In this way, reserpine-inducing mitochondrial dysfunction and increased production of ROI contribute to the development and maintenance of nociceptive, fatigue, and depressive-like behaviours.

Topics: Animals; Behavior, Animal; Depression; Disease Models, Animal; Fatigue; Fibromyalgia; Male; Mice; Mitochondria; Models, Biological; Muscles; Nociception; Oxidation-Reduction; Reserpine; Spinal Cord; Ubiquinone

Preeclampsia has ranked as one of the leading causes of both maternal and prenatal morbidity and mortality around the world. The hypotensive effect of coenzyme Q10 has been widely reported in preeclampsia rat model. However, the detailed mechanism remains unclear.. L-NAME was utilized to establish the preeclampsia rat model. Biomarker assessments were performed to identify the levels of vascular factors including soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PlGF), the circulating cytokines including interleukin 6, tumor necrosis factor α and interleukin 1β, and oxidative stress factors including malondialdehyde, H. Coenzyme Q10 treatment decreased the blood pressure in rat model with preeclampsia by regulating the circulating levels of sFlt-1 and PlGF. Coenzyme Q10 attenuated serum and placental inflammation and oxidative stress in L-NAME-induced preeclampsia rats. Coenzyme Q10 activated the placental Nrf2/HO-1 pathway in L-NAME-induced preeclampsia rats.. Coenzyme Q10 attenuated placental inflammatory and oxidative stress, thereby protecting the rats against preeclampsia by activating the Nrf2/HO-1 pathway.

Topics: Animals; Disease Models, Animal; Female; Heme Oxygenase (Decyclizing); NF-E2-Related Factor 2; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Signal Transduction; Ubiquinone

Topics: Animals; Anti-Inflammatory Agents; Brain; Brain Edema; Cell Line; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Inflammasomes; Mice, Inbred C57BL; Microglia; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Organophosphorus Compounds; Phenotype; Reactive Oxygen Species; Signal Transduction; Ubiquinone

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a fat-soluble antioxidant. Although CoQ10 has not been approved as medication by the Food and Drug Administration, it is widely used in dietary supplements. Some studies have shown that CoQ10 has anti-inflammatory effects on various autoimmune disorders. In this study, we investigated the anti-inflammatory effects of liposome/gold hybrid nanoparticles encoded with CoQ10 (LGNP-CoQ10). Both CoQ10 and LGNP-CoQ10 were administered orally to mice with collagen-induced arthritis (CIA) for 10 weeks. The inflammation pathology of joint tissues of CIA mice was then analyzed using hematoxylin and eosin and Safranin O staining, as well as immunohistochemistry analysis. We obtained immunofluorescence staining images of spleen tissues using confocal microscopy. We found that pro-inflammatory cytokines were significantly decreased in LGNP-CoQ10 injected mice. Th17 cell and phosphorylated STAT3-expressed cell populations were also decreased in LGNP-CoQ10 injected mice. When human peripheral blood mononuclear cells (PBMCs) were treated with CoQ10 and LGNP-CoQ10, the IL-17 expression of PBMCs in the LGNP-CoQ10-treated group was significantly reduced. Together, these results suggest that LGNP-CoQ10 has therapeutic potential for the treatment of rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Arthritis, Experimental; Arthritis, Rheumatoid; Autoimmune Diseases; Cell Line; Cytokines; Disease Models, Animal; Gold; Humans; Inflammation; Interleukin-17; Leukocytes, Mononuclear; Liposomes; Male; Metal Nanoparticles; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; STAT3 Transcription Factor; T-Lymphocytes, Regulatory; Th17 Cells; Ubiquinone

Sepsis increases the risk of the liver injury development. According to the research works, coenzyme Q10 exhibits hepatoprotective properties in vivo as well as in vitro. Current work aimed at investigating the protective impacts of coenzyme Q10 against liver injury in septic BALB/c mice. The male BALB/c mice were randomly segregated into 4 groups: the control group, the coenzyme Q10 treatment group, the puncture and cecal ligation group, and the coenzyme Q10+cecal ligation and puncture group. Cecal ligation and puncture was conducted after gavagaging the mice with coenzyme Q10 during two weeks. Following 48 h postcecal ligation and puncture, we estimated hepatic biochemical parameters and histopathological changes in hepatic tissue. We evaluated the expression of factors associated with autophagy, pyroptosis, and inflammation. Findings indicated that coenzyme Q10 decreased the plasma levels in alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase in the cecal ligation and puncture group. Coenzyme Q10 significantly inhibited the elevation of sequestosome-1, interleukin-1

Topics: Alanine Transaminase; Animals; Autophagy; Beclin-1; Body Weight; Disease Models, Animal; Gene Expression Regulation; Immunohistochemistry; Inflammation; Interleukin-6; Liver; Liver Diseases; Male; Mice; Mice, Inbred BALB C; Pyroptosis; Sepsis; Tumor Necrosis Factor-alpha; Ubiquinone; Up-Regulation

We aimed to create mechanic optic nerve injury model in rats and investigate the neuroprotective effects of topical Coenzyme Q10 + Vitamin E (CoQ + Vit.E) molecules on retinal ganglion cells.. Mechanic optic nerve injury model was created in the right eyes of rats (n = 12). Rats were divided into two groups: glaucoma model with sham treatment and topical CoQ + Vit.E treatment. Treatment was applied for 4 weeks. Glial fibrillary acidic protein, Brn-3a antibody, and anti-Iba1 were examined by immunohistochemistry. Glial fibrillary acidic protein, Bax, Bcl-xL, and Tfam protein expression were measured by Western blot analysis.. The number of Brn-3a-positive retinal ganglion cell was 15.0 ± 1.0 (min: 14, max: 16) in sham treatment group and 22.2 ± 4.8 (min: 18, max: 29) in topical CoQ10 + Vit.E treatment group. The protection of Brn-3a in CoQ10 + Vit.E was statistically significant (p < 0.05). Glial fibrillary acidic protein-positive astroglial counts were recorded as 11.7 ± 2.1 (min: 10, max: 14) in sham treatment and 2.5 ± 1.5 (min: 1, max: 4) in topical CoQ10 + Vit.E treatment group (p < 0.05). Topical CoQ10 + Vit.E treatment also decreased Iba1 expression in the retina of mechanic optic nerve injury groups. CoQ10 + Vit.E treatment prevented apoptotic cell death by increasing Bcl-xL protein expression. Also, CoQ10 + Vit.E preserved Tfam protein expression in the retina.. This study has shown that in glaucoma treatment the neuron protecting effect of topical CoQ10 + Vit.E molecules can be valuable.

Topics: Administration, Ophthalmic; Animals; bcl-2-Associated X Protein; bcl-X Protein; Blotting, Western; Calcium-Binding Proteins; Disease Models, Animal; Drug Combinations; Glaucoma; Glial Fibrillary Acidic Protein; Immunohistochemistry; Male; Microfilament Proteins; Neuroprotective Agents; Ophthalmic Solutions; Optic Nerve Injuries; Rats; Rats, Wistar; Retinal Ganglion Cells; Transcription Factor Brn-3A; Ubiquinone; Vitamin E

Can we use a mitochondrial-targeted antioxidant (Mitoquinone) during in vitro embryo culture to rescue developmental competence of oocytes matured under lipotoxic conditions, exhibiting mitochondrial dysfunction and oxidative stress?. Supplementation of embryo culture media with Mitoquinone reduced oxidative stress and prevented mitochondrial uncoupling in embryos derived from metabolically compromised oocytes in vitro, leading to higher blastocyst rates and lower blastomeric apoptosis.. Maternal metabolic disorders, such as obesity and type-II diabetes are associated with hyperlipidemia and elevated free fatty acid (FFA) concentrations in the ovarian follicular fluid (FF). Oocyte maturation under these lipotoxic conditions results in increased oxidative stress levels, mitochondrial dysfunction, reduced developmental competence and disappointing IVF results.. A well-described bovine oocyte IVM model was used, where a pathophysiologically relevant elevated FF concentrations of palmitic acid (PA; 150 μM or 300 μM) were added to induce oxidative stress. After fertilization (Day 0, D0), zygotes were in vitro cultured (IVC, from D1 to D8) in standard fatty acid-free media in the presence or absence of Mitoquinone or its carrier triphenyl-phosphonium.. Embryo cleavage and fragmentation (D2) and blastocyst rates (D8) were recorded. Mitochondrial activity and oxidative stress in cleaved embryos at D2 were determined using specific fluorogenic probes and confocal microscopy. D8 blastocysts were used to (i) examine the expression of marker genes related to mitochondrial unfolded protein responses (UPRmt; HSPD1 and HSPE1), mitochondrial biogenesis (TFAM), endoplasmic reticulum (ER) UPR (ATF4, ATF6 and BiP) and oxidative stress (CAT, GPX1 and SOD2) using real time RT-PCR; (ii) determine cell differentiation and apoptosis using CDX-2 and cleaved caspase-3 immunostaining; and (iii) measure mtDNA copy numbers. This was tested in a series of experiments with at least three independent replicates for each, using a total of 2525 oocytes. Differences were considered significant if a P value was <0.05 after Bonferroni correction.. Exposure to PA during IVM followed by culture under control conditions resulted in a significant increase in oxidative stress in embryos at D2. This was associated with a significant reduction in mitochondrial inner membrane potential (uncoupling) compared with solvent control (P < 0.05). The magnitude of these effects was PA-concentration dependent. Consequently, development to the blastocysts stage was significantly hampered. Surviving blastocysts exhibited high apoptotic cell indices and upregulated mRNA expression indicating persistent oxidative stress, mitochondrial and ER UPRs. In contrast, supplementation of PA-derived zygotes with Mitoquinone during IVC (i) prevented mitochondrial uncoupling and alleviated oxidative stress at D2; and (ii) rescued blastocyst quality; normalized oxidative stress and UPR related genes and apoptotic cell indices (P > 0.01 compared with solvent control). Mitoquinone also improved blastocyst rate in PA-exposed groups, an effect that was dependent on PA concentration.. N/A.. This is a fundamental study performed using a bovine in vitro model using PA-induced lipotoxicity during oocyte maturation. PA is the most predominant FFA in the FF that is known to induce lipotoxicity; however, in vivo maturation in patients suffering from maternal metabolic disorders involve more factors that cannot be represented in one model. Nevertheless, focusing on the carryover oxidative stress as a known key factor affecting developmental competence, and considering the novel beneficial rescuing effects of Mitoquinone shown here, we believe this model is of high biological relevance.. Human oocytes collected for IVF treatments from patients with maternal metabolic disorders are vulnerable to lipotoxicity and oxidative stress during in vivo maturation. The results shown here suggest that mitochondrial targeted therapy, such as using Mitoquinone, during IVC may rescue the developmental competence and quality of these compromised oocytes. After further clinical trials, this may be a valuable approach to increase IVF success rates for infertile patients experiencing metabolic disorders.. This study was financially supported by a BOF/KP grant number 34399, from the University of Antwerp, Belgium. W.F.A.M. was supported by a postdoctoral fellowship from the Research Foundation-Flanders (FWO), grant number 12I1417N, Antwerp, Belgium. The Leica SP 8 confocal microscope used in this study was funded by the Hercules Foundation of the Flemish Government (Hercules grant AUHA.15.12). All authors have no financial or non-financial competing interests to declare.

Topics: Animals; Antioxidants; Cattle; Culture Media; Diabetes Mellitus, Type 2; Disease Models, Animal; Embryo, Mammalian; Embryonic Development; Female; Follicular Fluid; Humans; In Vitro Oocyte Maturation Techniques; Infertility, Female; Mitochondria; Obesity; Oocytes; Organophosphorus Compounds; Oxidative Stress; Palmitic Acid; Ubiquinone

Spinal cord injury (SCI) has always been considered to be a devastating problem that results in catastrophic dysfunction, high disability rate, low mortality rate, and huge cost for the patient. Stem cell-based therapy, especially using bone marrow mesenchymal stem cells (BMSCs), is a promising strategy for the treatment of SCI. However, SCI results in low rates of cell survival and a poor microenvironment, which limits the therapeutic efficiency of BMSC transplantation. Coenzyme Q10 (CoQ10) is known as a powerful antioxidant, which inhibits lipid peroxidation and scavenges free radicals, and its combined effect with BMSC transplantation has been shown to have a powerful impact on protecting the vitality of cells, as well as antioxidant and antiapoptotic compounds in SCI. Therefore, we aimed to evaluate whether CoQ10 could decrease oxidative stress against the apoptosis of BMSCs

Topics: Animals; Apoptosis; Bone Marrow Cells; Disease Models, Animal; Hydrogen Peroxide; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord Injuries; Ubiquinone

Alzheimer's disease (AD) is the most prevalent form of dementia and is associated with loss of memory, amyloid-beta plaque buildup, and neurofibrillary tangles. These features might be a result of neuronal cell death in the cerebral cortex and hippocampal regions of the brain. AD pathologies can be attributed to a variety of biochemical consequences including mitochondrial dysfunction, increased oxidative stress, and autophagy inhibition. Unfortunately, current therapeutics are limited only to symptomatic relief and do not halt the progression of neurodegeneration. Previous in vitro experiments have shown that a water-soluble formulation of coenzyme-Q

Topics: Alzheimer Disease; Animals; Autophagy; Beclin-1; Cell Death; Cellular Senescence; Cerebral Cortex; Disease Models, Animal; Fibroblasts; Humans; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 8; Mutation; Neuroprotection; Presenilin-1; Ubiquinone; Up-Regulation

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the

Topics: Animals; Brain; Disease Models, Animal; Energy Metabolism; Histocytochemistry; Hydroxybenzoates; Mice; Mitochondrial Encephalomyopathies; Neuroprotective Agents; Salicylic Acid; Survival Analysis; Treatment Outcome; Ubiquinone

Mitochondrial NADP

Topics: Animals; Apoptosis; Biomarkers; Disease Models, Animal; Fluorescent Antibody Technique; Hair Cells, Auditory; Hearing Loss, Sensorineural; Homozygote; Immunohistochemistry; Isocitrate Dehydrogenase; Mice; Mice, Knockout; Mitochondria; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Spiral Ganglion; Ubiquinone

Increasing evidence indicates that mitochondrial-associated redox signaling contributes to the pathophysiology of heart failure (HF). The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is capable of modifying mitochondrial signaling and has shown beneficial effects on HF-dependent mitochondrial dysfunction. However, the potential therapeutic impact of MitoQ-based mitochondrial therapies for HF in response to pressure overload is reliant upon demonstration of improved cardiac contractile function and suppression of deleterious cardiac remodeling. Using a new (patho)physiologically relevant model of pressure overload-induced HF we tested the hypothesis that MitoQ is capable of ameliorating cardiac contractile dysfunction and suppressing fibrosis. To test this C57BL/6J mice were subjected to left ventricular (LV) pressure overload by ascending aortic constriction (AAC) followed by MitoQ treatment (2 µmol) for 7 consecutive days. Doppler echocardiography showed that AAC caused severe LV dysfunction and hypertrophic remodeling. MitoQ attenuated pressure overload-induced apoptosis, hypertrophic remodeling, fibrosis and LV dysfunction. Profibrogenic transforming growth factor-β1 (TGF-β1) and NADPH oxidase 4 (NOX4, a major modulator of fibrosis related redox signaling) expression increased markedly after AAC. MitoQ blunted TGF-β1 and NOX4 upregulation and the downstream ACC-dependent fibrotic gene expressions. In addition, MitoQ prevented Nrf2 downregulation and activation of TGF-β1-mediated profibrogenic signaling in cardiac fibroblasts (CF). Finally, MitoQ ameliorated the dysregulation of cardiac remodeling-associated long noncoding RNAs (lncRNAs) in AAC myocardium, phenylephrine-treated cardiomyocytes, and TGF-β1-treated CF. The present study demonstrates for the first time that MitoQ improves cardiac hypertrophic remodeling, fibrosis, LV dysfunction and dysregulation of lncRNAs in pressure overload hearts, by inhibiting the interplay between TGF-β1 and mitochondrial associated redox signaling.

Topics: Animals; Apoptosis; Biomarkers; Cardiomegaly; Disease Models, Animal; Echocardiography; Fibroblasts; Fibrosis; Heart Failure; Immunohistochemistry; Male; Mice; Models, Biological; Myocardium; Organophosphorus Compounds; Signal Transduction; Stress, Mechanical; Transforming Growth Factor beta; Ubiquinone; Ventricular Dysfunction, Left; Ventricular Remodeling

Glaucoma is a multifactorial neurodegenerative disorder and one of the leading causes of irreversible blindness globally and for which intraocular pressure is the only modifiable risk factor. Although neuroprotective therapies have been suggested to have therapeutic potential, drug delivery for the treatment of ocular disorders such as glaucoma remains an unmet clinical need, further complicated by poor patient compliance with topically applied treatments. In the present study we describe the development of multi-loaded PLGA-microspheres (MSs) incorporating three recognised neuroprotective agents (dexamethasone (DX), melatonin (MEL) and coenzyme Q10 (CoQ10)) in a single formulation (DMQ-MSs) to create a novel sustained-release intraocular drug delivery system (IODDS) for the treatment of glaucoma. MSs were spherical, with a mean particle size of 29.04 ± 1.89 μm rendering them suitable for intravitreal injection using conventional 25G-32G needles. >62% incorporation efficiency was achieved for the three drug cargo and MSs were able to co-deliver the encapsulated active compounds in a sustained manner over 30-days with low burst release. In vitro studies showed DMQ-MSs to be neuroprotective in a glutamate-induced cytotoxicity model (IC

Topics: Animals; Dexamethasone; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Liberation; Drug Therapy, Combination; Glaucoma; Humans; Injections, Intraocular; Male; Melatonin; Microspheres; Neuroprotective Agents; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Retina; Transcription Factor Brn-3B; Treatment Outcome; Ubiquinone

Oxidative stress plays a key role in contributing to β-amyloid (Aβ) deposition in Alzheimer's disease (AD). Coenzyme Q10 (Q10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals. In this study, we investigated the neuroprotective effects of Q10 on Aβ-induced impairment in hippocampal long-term potentiation (LTP), a widely researched model of synaptic plasticity, which occurs during learning and memory, in a rat model of AD. In this study, 50 adult male Wistar rats were assigned to five groups: control group (saline); sham group; intraventricular PBS injection, Aβ group; intraventricular Aβ injection, Q10 group; and Q10 via oral gavage and Q10 + Aβ group. Q10 was administered via oral gavage, once a day, for 3 weeks before and 3 weeks after the Aβ injection. After the treatment period, in vivo electrophysiological recordings were performed to quantify the excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the hippocampal dentate gyrus. LTP was created by a high-frequency stimulation of the perforant pathway. Following LTP induction, the EPSP slope and PS amplitude were significantly diminished in Aβ-injected rats, compared with sham and control rats. Q10 treatment of Aβ-injected rats significantly attenuated these decreases, suggesting that Q10 reduces the effects of Aβ on LTP. Aβ significantly increased serum malondialdehyde levels and total oxidant levels, whereas Q10 supplementation significantly reversed these parameters and increased total antioxidant capacity levels. The present findings suggested that Q10 treatment offers neuroprotection against the detrimental effects of Aβ on hippocampal synaptic plasticity via its antioxidant activity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Dentate Gyrus; Disease Models, Animal; Excitatory Postsynaptic Potentials; Hippocampus; Long-Term Potentiation; Male; Memory; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Rats; Rats, Wistar; Synaptic Transmission; Temporal Lobe; Ubiquinone

The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown.. We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9. Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9. These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).

Topics: Animals; Autophagy; Cell Respiration; Disease Models, Animal; Gene Expression Profiling; Humans; Metabolomics; Mice; Mitochondria; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Phenotype; Sirolimus; Treatment Outcome; Ubiquinone

Type 2 diabetic patients possess a two to four fold-increased risk for Cardiovascular Diseases (CVD). Hyperglycemia, oxidative stress associated with endothelial dysfunction and dyslipidemia are regarded as pro-atherogenic mechanisms of CVD. In this study, high-fat diet-induced diabetic and non-diabetic vervet monkeys were treated with 90 mg/kg of aspalathin-rich green rooibos extract (Afriplex GRT) for 28 days, followed by a 1-month wash-out period. Supplementation showed improvements in both the intravenous glucose tolerance test (IVGTT) glycemic area under curve (AUC) and total cholesterol (due to a decrease of the low-density lipoprotein [LDL]) values in diabetics, while non-diabetic monkeys benefited from an increase in high-density lipoprotein (HDL) levels. No variation of plasma coenzyme Q10 (CoQ

Topics: Animals; Biomarkers; Blood Glucose; Chalcones; Chlorocebus aethiops; Cholesterol, LDL; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Female; Hypoglycemic Agents; Lipids; Lipoproteins, LDL; Male; Oxidation-Reduction; Oxidative Stress; Plant Extracts; Ubiquinone

Coenzyme Q

Topics: Administration, Oral; Animals; Antioxidants; Biological Availability; Catalepsy; Disease Models, Animal; Emulsions; Female; Male; Microscopy, Electron; Movement; Oxidative Stress; Parkinson Disease; Rats; Rats, Wistar; Refractometry; Solubility; Surface-Active Agents; Swimming; Thiobarbituric Acid Reactive Substances; Ubiquinone; Viscosity

Parkinson's disease (PD) affects ∼1-2% of the elderly population. Development of a neuroprotective therapy that may be initiated early in the course of the disease to retard/prevent disease progression is highly desirable. This study aimed to investigate prophylactic treatment with coenzyme Q10 (CoQ10) before paraquat (PQ) exposure, a herbicide known to increase the risk for PD, to attain neuroprotection. In addition, therapeutic intervention with CoQ10 in mice already exposed to PQ (24 h) might halt ongoing neurodegeneration and behavioural deterioration. PD was induced experimentally in mice by an injection of PQ (10 mg/kg, intraperitoneal), twice a week for 3 consecutive weeks, either before or after the initiation of treatment with CoQ10 (200 mg/kg). The results of the sustained supplementation with CoQ10, prophylactically and therapeutically, were compared with L-DOPA (100 mg/kg). A battery of behavioural tests was performed, in addition to estimation of protein carbonyl in the brain. CoQ10 elicited a remarkable improvement in most of the behavioural tests and decreased protein carbonyl content in the brain, particularly when it was initiated before rather than after PQ induction of PD. Therefore, CoQ10, which protects against mitochondrial damage, may be beneficial in slowing the progression of PD, particularly when initiated as prophylactic treatment.

Topics: Animals; Disease Models, Animal; Levodopa; Male; Mice; Mitochondria; Neurons; Neuroprotective Agents; Oxidative Stress; Paraquat; Parkinson Disease; Protein Carbonylation; Ubiquinone

 Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Microglia; Mutation; Nerve Tissue Proteins; Peptide Fragments; Presenilin-1; Ubiquinone; Vitamins

Primary disorders of the human coenzyme Q

Topics: Animals; Apoptosis; Ataxia; Biosynthetic Pathways; Cytochrome P-450 Enzyme System; Disease Models, Animal; Humans; Hydroxybenzoates; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Pyrimidines; Solubility; Treatment Outcome; Ubiquinone; Vitamins

Probiotic complex, zinc, and coenzyme Q10 (CoQ10) are recognized dietary supplements with an anti-inflammatory role. Although these supplementations are individually known to benefit rheumatoid arthritis (RA), there is no evidence suggesting any synergic effect. The primary goal of this study is to determine whether probiotic complex, zinc, and CoQ10 attenuate the development of collagen-induced arthritis (CIA). The combination of probiotic complex, zinc, and CoQ10 reduced CIA severity by downregulating the levels of IgG, IgG1, and IgG2a in serum. Joint inflammation, bone destruction, and cartilage damage were also improved by the complex. There was a decrease in the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17, and vascular endothelial growth factor (VEGF) in the joint synovium. The balance between helper T 17 (Th17) cells and regulatory T (Treg) cells was shown to be controlled reciprocally by the complex. These findings suggest that the combination of probiotic complex, zinc, and CoQ10 can ameliorate the development of CIA by inhibiting the expression of proinflammatory cytokines, and is thus an important therapeutic candidate for RA treatment.

Topics: Animals; Arthritis, Rheumatoid; Disease Models, Animal; Drug Therapy, Combination; Humans; Interleukin-17; Interleukin-6; Male; Mice; Mice, Inbred DBA; Probiotics; T-Lymphocytes, Regulatory; Th17 Cells; Tumor Necrosis Factor-alpha; Ubiquinone; Zinc

Heart failure remains a major public-health problem with an increase in the number of patients worsening from this disease. Despite current medical therapy, the condition still has a poor prognosis. Heart failure is complex but mitochondrial dysfunction seems to be an important target to improve cardiac function directly. Our goal was to analyze the effects of MitoQ (100 µM in drinking water) on the development and progression of heart failure induced by pressure overload after 14 weeks. The main findings are that pressure overload-induced heart failure in rats decreased cardiac function in vivo that was not altered by MitoQ. However, we observed a reduction in right ventricular hypertrophy and lung congestion in heart failure animals treated with MitoQ. Heart failure also decreased total mitochondrial protein content, mitochondrial membrane potential in the intermyofibrillar mitochondria. MitoQ restored membrane potential in IFM but did not restore mitochondrial protein content. These alterations are associated with the impairment of basal and stimulated mitochondrial respiration in IFM and SSM induced by heart failure. Moreover, MitoQ restored mitochondrial respiration in heart failure induced by pressure overload. We also detected higher levels of hydrogen peroxide production in heart failure and MitoQ restored the increase in ROS production. MitoQ was also able to improve mitochondrial calcium retention capacity, mainly in the SSM whereas in the IFM we observed a small alteration. In summary, MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload, by decreasing hydrogen peroxide formation, improving mitochondrial respiration and improving mPTP opening.

Topics: Animals; Antioxidants; Disease Models, Animal; Heart Failure; Mitochondria; Mitochondria, Heart; Organophosphorus Compounds; Rats; Ubiquinone

The cardioprotective effect of ubiquinol on the model of myocardium reperfusion injury in rats was investigated. The study was carried out using mature males of outbred rats. Myocardial ischemia-reperfusion injury was performed after 30-minute ligation of the left coronary artery followed by reperfusion. The main criteria for assessing the development of pathology included the results of electrocardiography, biochemical analysis of blood plasma, histological and histochemical study of the myocardium. Development of the reperfusion damage of the myocardium caused specific changes in non-treated animals. The best therapeutic effect on biochemical indices was provided by a drug with the known cardioprotective activity - Mexidolâ and the tested object ubiquinol at doses of 2-6 mg/kg. Evaluation of the results of electrocardiography allowed to confirm the development of ischemic myocardial damage in all groups. The results of histochemical and histological examination of the myocardium suggest a high cardioprotective activity of ubiquinol at a dose of 3 mg/kg and a potential cardioprotective effect of ubiquinol in doses closest to the therapeutic doses of 2 and 6 mg/kg. Ubiquinol is a dose 9 mg/kg showed signs of prooxidant activity, manifested in the form of aggravation of reperfusion injury of the myocardium. The most effective in the conditions of experimental pathology is 1% solution of ubiquinol, at a dose of 3 mg/kg, whose cardioprotective effect is comparable or higher than that for the reference drug Mexidolâ at the therapeutic dose. In doses that are greater than therapeutic ubiquinol is able to act as a pro-oxidant.. V stat'e predstavleny rezul'taty éksperimental'nogo doklinicheskogo issledovaniia, tsel'iu kotorogo iavlialas' otsenka kardioprotektornogo deĭstviia 1% rastvora ubikhinola pri vnutrivennom vvedenii v usloviiakh éksperimental'nogo reperfuzionnogo povrezhdeniia miokarda krys. Issledovanie provodilos' s ispol'zovaniem polovozrelykh samtsov autbrednykh krys, modelirovanie ishemii-reperfuzii miokarda osushchestvlialos' putem 30-minutnogo ligirovaniia levoĭ koronarnoĭ arterii s posleduiushcheĭ reperfuzieĭ. V kachestve kriteriev otsenki razvitiia patologii ispol'zovali rezul'taty élektrokardiografii, biokhimicheskogo analiza plazmy krovi, gistologicheskoe i gistokhimicheskoe issledovanie miokarda. Na fone razvitiia reperfuzionnogo povrezhdeniia miokarda razvivalis' kharakternye priznaki ishemii miokarda u zhivotnykh, ne poluchavshikh lechenie. Nailuchshiĭ terapevticheskiĭ éffekt v otnoshenii biokhimicheskikh pokazateleĭ okazali standartnyĭ ob"ekt Meksidolâ i testiruemyĭ ob"ekt Ubikhinol v dozakh 2-6 mg/kg. Otsenka rezul'tatov élektrokardiografii vo vtorom standartnom otvedenii pozvolila podtverdit' razvitie ishemicheskogo povrezhdeniia miokarda vo vsekh gruppakh. Rezul'taty gistokhimicheskogo i gistologicheskogo issledovaniia miokarda pozvoliaiut sdelat' vyvod o vysokoĭ kardioprotektornoĭ aktivnosti ubikhinola v doze 3 mg/kg i potentsial'nom kardioprotektornom éffekte ubikhinola v dozakh, naibolee blizkikh k terapevticheskoĭ – 2 i 6 mg/kg. Ubikhinol v doze 9 mg/kg proiavil priznaki prooksidantnoĭ aktivnosti, proiavivshiesia v vide usugubleniia razvitiia reperfuzionnogo porazheniia miokarda. Naibolee éffektivnymi v usloviiakh éksperimental'noĭ patologii iavliaetsia preparat ubikhinol, 1% rastvor, v doze 3 mg/kg, kardioprotektornyĭ éffekt kotorogo sopostavim, libo prevyshaet takovoĭ dlia referentnogo preparata Meksidolâ v terapevticheskoĭ doze. V dozakh, mnogokratno prevyshaiushchikh terapevticheskuiu, ubikhinol sposoben vystupat' v roli prooksidanta.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Heart; Male; Myocardial Reperfusion Injury; Myocardium; Rats; Ubiquinone

Intrauterine growth restriction, a common consequence of prenatal hypoxia, is a leading cause of fetal morbidity and mortality with a significant impact on population health. Hypoxia may increase placental oxidative stress and lead to an abnormal release of placental-derived factors, which are emerging as potential contributors to developmental programming. Nanoparticle-linked drugs are emerging as a novel method to deliver therapeutics targeted to the placenta and avoid risking direct exposure to the fetus. We hypothesize that placental treatment with antioxidant MitoQ loaded onto nanoparticles (nMitoQ) will prevent the development of cardiovascular disease in offspring exposed to prenatal hypoxia. Pregnant rats were intravenously injected with saline or nMitoQ (125 μM) on gestational day (GD) 15 and exposed to either normoxia (21% O

Topics: Age Factors; Animals; Antioxidants; Cardiovascular Diseases; Disease Models, Animal; Female; Fetal Hypoxia; Gestational Age; Hemodynamics; Male; Maternal Exposure; Myocardial Contraction; Nanoparticles; Organophosphorus Compounds; Oxidative Stress; Placenta; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley; Sex Factors; Ubiquinone; Ventricular Function, Left

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNc). Although mitochondrial dysfunction is the critical factor in the pathogenesis of PD, the underlying molecular mechanisms are not well understood, and as a result, effective medical interventions are lacking. Mitochondrial fission and fusion play important roles in the maintenance of mitochondrial function and cell viability. Here, we investigated the effects of MitoQ, a mitochondria-targeted antioxidant, in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo PD models. We observed that 6-OHDA enhanced mitochondrial fission by decreasing the expression of Mfn1, Mfn2 and OPA1 as well as by increasing the expression of Drp1 in the dopaminergic (DA) cell line SN4741. Notably, MitoQ treatment particularly upregulated the Mfn2 protein and mRNA levels and promoted mitochondrial fusion in the presence of 6-OHDA in a Mfn2-dependent manner. In addition, MitoQ also stabilized mitochondrial morphology and function in the presence of 6-OHDA, which further suppressed the formation of reactive oxygen species (ROS), as well as ameliorated mitochondrial fragmentation and cellular apoptosis. Moreover, the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was attributed to the upregulation of Mfn2 induced by MitoQ. Consistent with these findings, administration of MitoQ in 6-OHDA-treated mice significantly rescued the decrease of Mfn2 expression and the loss of DA neurons in the SNc. Taken together, our findings suggest that MitoQ protects DA neurons in a 6-OHDA induced PD model by activating PGC-1α to enhance Mfn2-dependent mitochondrial fusion.

Topics: Animals; Antioxidants; Cell Line; Cell Survival; Disease Models, Animal; Dopaminergic Neurons; GTP Phosphohydrolases; Humans; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Dynamics; Organophosphorus Compounds; Oxidopamine; Parkinson Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; RNA, Messenger; Substantia Nigra; Ubiquinone; Up-Regulation

Coenzyme Q. Our study confirmed the strong anti-inflammatory effects of coenzyme Q. There is significant synergy between coenzyme Q

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Autoimmune Diseases; Cell Line, Tumor; Cytokines; Disease Models, Animal; Drug Synergism; Female; Glucans; Humans; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Phagocytosis; RAW 264.7 Cells; Ubiquinone

Nitrogen mustard (NM) is a devastating casualty agent in chemical warfare. There is no effective antidote to treat NM-induced ocular injury. We aimed to assess the effects of proanthocyanidin (PAC) and coenzyme Q10 (CoQ10) on NM-induced ocular injury.. Eighteen male rats were divided into the following 4 groups: NM, NM + PAC, NM + CoQ10, and control. The 3 NM groups received a single dose of NM (0.02 mg/μL) on the right eye to induce ocular injury. The control group received saline only. Thirty minutes after the application of NM, the NM + PAC group received PAC (100 mg/kg) via gastric gavage, while the NM + CoQ10 group received CoQ10 (10 mg/kg) via intraperitoneal injection. PAC and CoQ10 were administered once a day for 5 consecutive days. The rats were then sacrificed. Macroscopic images of the eyes were examined and eye tissues were collected for histology.. The treatment groups were compared to the control group with regard to both corneal opacity and lid injury scores. The findings were not significantly different for both the NM + PAC and NM + CoQ10 groups. In both the NM + PAC and NM + CoQ10 groups, the histological changes seen in the NM group demonstrated improvement.. Our results indicate that PAC and CoQ10 treatments have therapeutic effects on NM-induced ocular injury in a rat model. PAC and CoQ10 may be novel options in patients with NM-induced ocular injury.

Topics: Animals; Antioxidants; Burns, Chemical; Chemical Warfare Agents; Disease Models, Animal; Eye Injuries; Male; Mechlorethamine; Proanthocyanidins; Random Allocation; Rats; Rats, Sprague-Dawley; Ubiquinone

Topics: Animals; Antioxidants; Apoptosis; Astrocytes; bcl-2-Associated X Protein; bcl-Associated Death Protein; bcl-X Protein; Caspase 3; Cell Survival; Disease Models, Animal; Female; Gene Expression Regulation; Intraocular Pressure; Mice; Mice, Inbred C57BL; Microglia; Oxidative Stress; Phosphorylation; Reactive Oxygen Species; Reperfusion Injury; Retinal Degeneration; Retinal Ganglion Cells; Signal Transduction; Ubiquinone

Berberine and coenzyme Q10 (CoQ10) are agents with anti-inflammatory and antioxidant characteristics. The purpose of this study was to investigate the effectiveness of berberine and CoQ10 on allergic rhinitis.. This study involved 30 Sprague-Dawley rats, and allergic rhinitis model was established with induction of ovalbumin. Rats were randomized into five groups. The first represented the control group, in which no allergy was established. The second represented the allergy group, in which allergy was induced but no treatment was given. In the remaining three groups, following induction of allergy, desloratadine at a dose of 10 mg/kg was given to Group 3, 100 mg/kg dose of berberine to Group 4, and 20 mg/kg dose of CoQ10 to Group 5. Nasal symptom scores, and plasma immunoglobulin-E, interleukin (IL)-4, IL-13, malondialdehyde (MDA) and nitric oxide (NO) levels were examined at the end of the study. Rats' nasal tissues were also subjected to histopathological immunohistochemical examination.. Nasal symptom scores, and plasma immunoglobulin-E, IL-4, IL-13, MDA and NO levels increased significantly in rats with induced allergic rhinitis. Berberine and CoQ10 significantly reduced these elevated levels. CoQ10 was also found as effective as desloratadin in terms of nasal symptom scores and biochemical parameters. At histopathological examination, severe allergic inflammation was observed in rats from allergic rhinitis group. At all treatment groups, the histopathological changes were significantly improved and only a mild inflammation was determined. Also, immunochemistry showed a significant improvement in all three treatment groups. Coenzyme Q10 and berberine were both effective in suppressing allergy symptoms.. We think that berberine and coenzyme Q10 can usefully be employed as therapy due to their antioxidant and anti-inflammatory effects in an experimentally induced allergic rhinitis model.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Berberine; Disease Models, Animal; Histamine H1 Antagonists, Non-Sedating; Immunoglobulin E; Interleukin-13; Interleukin-4; Loratadine; Malondialdehyde; Nitric Oxide; Random Allocation; Rats, Sprague-Dawley; Rhinitis, Allergic; Ubiquinone

Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q

Topics: Alkyl and Aryl Transferases; Animals; Antioxidants; Ataxia; Disease Models, Animal; HeLa Cells; Humans; Hydrogen Sulfide; Kidney; Metabolic Networks and Pathways; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Oxidation-Reduction; Oxidative Stress; Oxidoreductases Acting on Sulfur Group Donors; Reactive Oxygen Species; Ubiquinone

Topics: Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Antrodia; Arginine; Arterioles; Biological Products; Biomarkers; Blood Pressure; Disease Models, Animal; Hypertension; Inflammation; Kidney; Kidney Diseases; Male; Malondialdehyde; NG-Nitroarginine Methyl Ester; Oxidative Stress; Rats, Wistar; Ubiquinone

Topics: Animals; Autophagy; Blotting, Western; Cell Survival; Disease Models, Animal; Flow Cytometry; Mice; Mitochondria, Muscle; Mitochondrial Diseases; Oxidative Stress; Physical Conditioning, Animal; Ubiquinone

Clinical studies have identified patients with nephrotic syndrome caused by mutations in genes involved in the biosynthesis of coenzyme Q

Topics: Alkyl and Aryl Transferases; Alleles; Animals; Autophagy; Cell Line; Cells, Cultured; Disease Models, Animal; Gene Silencing; Humans; Mitochondria; Mitophagy; Nephrotic Syndrome; Organisms, Genetically Modified; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Ubiquinone; Vitamins

Anaesthesia can induce cognitive deficiency in young rodents and monkeys. Mitochondrial dysfunction contributes to the anaesthesia-induced neurotoxicity and neurobehavioural deficits. We therefore assessed the effects of the mitochondrial energy enhancer coenzyme Q 10 (CoQ 10 ) on anaesthesia-induced cognitive deficiency in young mice to investigate the role of mitochondrial dysfunction.. Young mice ( n =134) were randomly assigned into the following four groups: control plus corn oil vehicle (60% oxygen); 3% sevoflurane [2 h daily on postnatal day (P) 6, 7, and 8] plus vehicle; CoQ 10 (50 mg kg -1 ) plus vehicle; or 3% sevoflurane plus CoQ 10 plus vehicle. We determined cognitive function using the Morris water maze at P31-P37. We quantified brain postsynaptic density protein-95, the presynaptic marker synaptophysin, adenosine triphosphate, reactive oxygen species, and mitochondrial membrane potential at P8 and P37.. Coenzyme Q 10 reduced sevoflurane-induced cognitive deficiency in young mice ( F =0.90, P =0.49, n =10-16) and attenuated sevoflurane-induced reductions in postsynaptic density protein-95 ( F =10.56, P <0.01, n =6), synaptophysin ( F =8.44, P =0.01, n =6), adenosine triphosphate ( F =4.34, P =0.05, n =9), and mitochondrial membrane potential ( F =11.43, P <0.01, n =6), but not sevoflurane-induced increases in reactive oxygen species ( F =1.17, P =0.20, n =6), in brain.. These data suggest that CoQ 10 reduces sevoflurane-induced cognitive deficiency by mitigating sevoflurane-induced mitochondrial dysfunction, the reduction in adenosine triphosphate, and synaptic dysfunction. Coenzyme Q 10 could provide an approach to reduce the neurotoxicity of anaesthesia in the developing brain.

Topics: Anesthetics, Inhalation; Animals; Cognition Disorders; Disease Models, Animal; Female; Male; Mice; Mice, Inbred C57BL; Sevoflurane; Ubiquinone; Vitamins

Coenzyme Q10 (CoQ10) is a naturally occurring, lipid-soluble antioxidant and an essential electron carrier in the mitochondrial respiratory chain. In sepsis, CoQ10 deficiency induced by mitochondrial failure can lead to hypoxia, hypoperfusion, oxidative organ damage and finally death. We aimed to investigate the effects of CoQ10 on survival, mesenteric artery blood flow (MABF), vascular reactivity, oxidative and inflammatory injuries in cecal ligation and puncture (CLP)-induced sepsis.. Wistar rats were divided into Sham, CLP, Sham+CoQ10, CLP+CoQ10 subgroups. CoQ10 (10mg/kg/day) or vehicle (olive oil; 1mL/kg/day) was intraperitoneally injected for 15days. At 16th day, Sham or CLP operation was performed. 20h after the operations, MABF and phenylephrine responses of isolated aortic rings were measured. Tissue samples were obtained for histopathological and biochemical evaluations. Furthermore, survival rates were monitored throughout 96h.. CoQ10 prevented mesenteric hypoperfusion and aortic dysfunction induced by CLP. Survival rate was %0 at 46th h in CLP group, but in CLP+CoQ10 group it was 37.5% at the end of 96h. CLP-induced elevations of serum AST, ALT, LDH, BUN, Cr and inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) levels were blocked by CoQ10. CoQ10 restored the increased liver, lung, spleen and kidney malondialdehyde levels and as well as reduced liver and spleen glutathione levels. The protective effects of CoQ10 on multiple organ damage were also observed histopathologically.. CoQ10 showed protective effects in sepsis due to its preservative effects on mesenteric perfusion, aortic function and also its anti-inflammatory and antioxidative effects.

Topics: Animals; Aorta; Cecum; Cytokines; Disease Models, Animal; Female; Inflammation; Ligation; Malondialdehyde; Mesenteric Ischemia; Protective Agents; Rats; Rats, Wistar; Renal Circulation; Sepsis; Survival Rate; Ubiquinone

Coenzyme Q10 (CoQ10) is a mitochondrial-targeted antioxidant with known neuroprotective activity. Its ocular effects when co-solubilised with α-tocopherol polyethylene glycol succinate (TPGS) were evaluated. In vitro studies confirmed that CoQ10 was significantly protective in different retinal ganglion cell (RGC) models. In vivo studies in Adult Dark Agouti (DA) rats with unilateral surgically-induced ocular hypertension (OHT) treated with either CoQ10/TPGS micelles or TPGS vehicle twice daily for three weeks were performed, following which retinal cell health was assessed in vivo using DARC (Detection of Apoptotic Retinal Cells) and post-mortem with Brn3a histological assessment on whole retinal mounts. CoQ10/TPGS showed a significant neuroprotective effect compared to control with DARC (p<0.05) and Brn3 (p<0.01). Topical CoQ10 appears an effective therapy preventing RGC apoptosis and loss in glaucoma-related models.

Topics: Animals; Disease Models, Animal; Male; Mitochondria; Neuroprotection; Neuroprotective Agents; Ocular Hypertension; Rats; Retinal Ganglion Cells; Treatment Outcome; Ubiquinone; Vitamin E

Oxidative stress contributes to the pathogenesis of propionic acidemia (PA), a life threatening disease caused by the deficiency of propionyl CoA-carboxylase, in the catabolic pathway of branched-chain amino acids, odd-number chain fatty acids and cholesterol. Patients develop multisystemic complications including seizures, extrapyramidal symptoms, basal ganglia deterioration, pancreatitis and cardiomyopathy. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species and oxidative damage, all of which have been documented in patients' samples and in a hypomorphic mouse model. Here we set out to investigate whether treatment with a mitochondria-targeted antioxidant, MitoQ, or with the natural polyphenol resveratrol, which is reported to have antioxidant and mitochondrial activation properties, could ameliorate the altered redox status and its functional consequences in the PA mouse model. The results show that oral treatment with MitoQ or resveratrol decreases lipid peroxidation and the expression levels of DNA repair enzyme OGG1 in PA mouse liver, as well as inducing tissue-specific changes in the expression of antioxidant enzymes. Notably, treatment decreased the cardiac hypertrophy marker BNP that is found upregulated in the PA mouse heart. Overall, the results provide in vivo evidence to justify more in depth investigations of antioxidants as adjuvant therapy in PA.

Topics: Administration, Oral; Amino Acids, Branched-Chain; Animals; Antioxidants; Disease Models, Animal; Heart; Humans; Lipid Peroxidation; Mice; Organophosphorus Compounds; Oxidative Stress; Propionic Acidemia; Resveratrol; Stilbenes; Ubiquinone

Coenzyme Q10 (CoQ10) is a powerful antioxidant substance synthesized in the body. The current study aimed to determine whether CoQ10 suppresses inflammation and inhibits p-STAT3 expression in an experimental colitis mouse model. The mice were orally fed with CoQ10 once a day for 13 days. Histological analysis of the colons was performed by immunohistochemistry. Expression of IL-17, FOXP3, p53, AMPK, and mTOR and activation of p-STAT3 and p-STAT5 in lymph node and spleen tissues were detected by confocal microscopy of stained tissue sections. The relative mRNA expression was measured with real-time PCR, and protein levels were examined by western blot. CoQ10 reduced the disease activity index score and the colon histological score. It also reduced inflammatory mediators in the colon and increased the colon length. The expression of IL-17 and p-STAT3 was decreased with CoQ10 treatment. In contrast, CoQ10 treatment increased the expression of p-AMPK and FOXP3. Expression of anti-inflammatory cytokines was shown to increase in colitis mice treated with CoQ10. These results suggested that CoQ10 may reduce the severity of colitis and suppress inflammation through the inhibition of p-STAT3 and IL-17. These results support the use of CoQ10 as a potential targeted therapy for the treatment of colitis.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Disease Models, Animal; Humans; Interleukin-17; Male; Mice; Mice, Inbred C57BL; STAT3 Transcription Factor; Th17 Cells; Ubiquinone

Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D); (ii) MitoQ (DMitoQ;0.6 mg/kg/day); (iii) Ramipril (DRam;3 mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db/db mice for 12 weeks (n = 11-13/group). Non-diabetic (C) db/m mice were followed concurrently. No therapy altered glycaemic control or body weight. By the study end, both monotherapies improved renal function, decreasing glomerular hyperfiltration and albuminuria. All therapies prevented tubulointerstitial collagen deposition, but glomerular mesangial expansion was unaffected. Renal cortical concentrations of ATP, ADP, AMP, cAMP, creatinine phosphate and ATP:AMP ratio were increased by diabetes and mostly decreased with therapy. A higher creatine phosphate:ATP ratio in diabetic kidney cortices, suggested a decrease in ATP consumption. Diabetes elevated glucose 6-phosphate, fructose 6-phosphate and oxidised (NAD+ and NADP+) and reduced (NADH) nicotinamide dinucleotides, which therapy decreased generally. Diabetes increased mitochondrial oxygen consumption (OCR) at complex II-IV. MitoQ further increased OCR but decreased ATP, suggesting mitochondrial uncoupling as its mechanism of action. MitoQ showed renoprotection equivalent to ramipril but no synergistic benefits of combining these agents were shown.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Mice; Molecular Targeted Therapy; Organophosphorus Compounds; Ramipril; Treatment Outcome; Ubiquinone

The purpose of this study was to compare the effects of thymoquinone and icodextrin in rats within the framework of an experimental adhesion model.. Rats were separated into three groups: (1) a control group consisting of rats that had 2 ml of isotonic solution administered intraperitoneally, (2) an ICO group administered with 2 ml of 4% icodextrin, and (3) a TQ group administered thymoquinone (10 mg/kg), all following cecal abrasion. The three groups underwent a reoperation on the 7th postoperative day. Hydroxyproline levels were analyzed in the resected adhesive tissues, and histopathological investigations were conducted. Blood samples were collected for biochemical analyses.. Fewer postoperative adhesions were observed in the ICO and TQ groups compared with the control group. A comparison of the TQ and ICO groups revealed lowers levels of postoperative adhesions in the TQ group. Compared with the control group, malondialdehyde, 8-OH-deoxyguanosine/deoxyguanosine (8-OHdG/10dG), Coenzyme Q10 (CoQ10), and CoenzymeQ10/reduced CoenzymeQ10 (CoQ10/CoQ10H) values were found to be lower in the TQ and ICO groups. When the TQ and ICO groups were compared with respect to their biochemical parameters, the results for all of the four parameters were found to be statistically significantly lower in the TQ group (P < 0.000). The levels of hydroxyproline in the control, ICO, and TQ groups were found to be (mean ± standard deviation) 502.25 ± 90.39 μg/g, 342.13 ± 66.61 μg/g, and 287.88 ± 49.59 μg/g, respectively.. A comparison of the antiadhesive effects of thymoquinone and icodextrin revealed thymoquinone to be more effective. These results indicate that thymoquinone is an efficient and strong antiadhesive molecule.

Topics: Animals; Benzoquinones; Disease Models, Animal; Glucans; Glucose; Humans; Icodextrin; Injections, Intraperitoneal; Male; Postoperative Complications; Rats; Rats, Wistar; Tissue Adhesions; Ubiquinone

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9

Topics: Animals; Ataxia; Blood Pressure; Cells, Cultured; Cerebrum; Disease Models, Animal; Fibroblasts; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Oxidation-Reduction; Quinone Reductases; Sulfides; Ubiquinone

Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.

Topics: Animals; Antioxidants; Cell Line; Diabetic Nephropathies; Disease Models, Animal; Epithelial Cells; Gene Expression Regulation; Glucose; Hypoglycemic Agents; Injections, Intraperitoneal; Kelch-Like ECH-Associated Protein 1; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Mitophagy; NF-E2-Related Factor 2; Organophosphorus Compounds; Protein Kinases; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Ubiquinone; Ubiquitin-Protein Ligases

An age-dependent model of the periodontium was reproduced to evaluate the effect of life-long feeding on a low coenzyme Q10 dosage in n-6, n-3 polyunsaturated fatty acid or monounsaturated fatty acid-based diets on periodontal tissues of young and old rats. Results shown that exacerbated age-related alveolar bone loss previously associated to n-6 polyunsaturated fatty acid diet was attenuated by coenzyme Q10 Gene expression analysis suggests that involved mechanisms might be related to a restored capacity of mitochondria to adapt to aging in gingival cells from rats fed on n-6 polyunsaturated fatty acid. In particular, this could be due to an age-related increase of the rate of mitochondrial biogenesis and a better oxidative and respiratory balance in these animals. From the nutritional and clinical point of view, it is noteworthy that supplementation with coenzyme Q10 could counteract the negative effects of n-6 polyunsaturated fatty acid on alveolar bone loss (a major feature of periodontitis) associated to age.

Topics: Alveolar Bone Loss; Animals; Diet; Disease Models, Animal; Fatty Acids, Omega-6; Male; Osteoporosis; Rats; Rats, Wistar; Ubiquinone; Vitamins

Doxorubicin (DXR) extravasation result with serious morbidity like skin ulceration and necrosis. The purpose of this study is to determine the protective effects of ozone, olive oil, dimethyl sulfoxide (DMSO), and coenzyme Q10 in the treatment of DXR-induced skin ulcers on rats. After an intradermal injection of DXR on a basis of an animal extravasation model, the materials were topically applied. The ulcer sizes were measured, and a punch biopsy was taken from the extravasation site in which the skin ulcers formed at the end of the experiment. The samples were analyzed for tumor necrosis factor alpha (TNF-α), interleukin 1-beta (IL1β), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzymes, and examined histopathologically. The ulcer sizes clearly decreased in the study groups, including DMSO, olive oil, ozone plus coenzyme Q10, and ozone plus olive oil groups in comparison with the control group with the exception of the coenzyme Q10 group. The malondialdehyde levels were lower in the DMSO, olive oil, ozone plus olive oil, and ozone plus coenzyme Q10 groups than they were in the control group, but they were not significantly different. The TNF-α level was lower in the DMSO, ozone plus olive oil, coenzyme Q10, and ozone plus coenzyme Q10 groups in comparison with the control group. There was no significant change in the SOD, GSH-Px, and IL1β levels in the study groups in comparison with the control and the sham groups. The ozone plus olive oil group could be considered to be an alternate therapy for skin ulcers due to DXR extravasation.

Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Biopsy; Dimethyl Sulfoxide; Disease Models, Animal; Doxorubicin; Extravasation of Diagnostic and Therapeutic Materials; Necrosis; Olive Oil; Oxidative Stress; Ozone; Rats; Skin; Skin Ulcer; Ubiquinone

Anti-oxidant coenzyme Q10 (Co-Q10) is commonly used in clinic. Recently, Co-Q10 was reported to antagonize TNF-α-induced inflammation and play a protective role in various inflammatory conditions. However, its role in dermatitis is unknown. Herein, RAW264.7 macrophage cell line was cultured with stimulation of TNF-α, and administration of Co-Q10 alleviated TNF-α-mediated inflammatory reaction in vitro. Furthermore, oxazolone-induced dermatitis mice model was established, and treatment of Co-Q10 markedly attenuated dermatitis phenotype in this mice model. Moreover, the protective role of Co-Q10 in vitro and in dermatitis was probably due to its repression on NF-κB signaling. Collectively, Co-Q10 may represent a potential molecular target for prevention and treatment of inflammatory skin diseases.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Dermatitis, Contact; Disease Models, Animal; Inflammation; Interleukin-1beta; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxazolone; Skin; Tumor Necrosis Factor-alpha; Ubiquinone

Topics: Administration, Oral; Anemia, Sickle Cell; Animals; Antioxidants; Astrocytes; Curcumin; Disease Models, Animal; Female; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Humans; Hyperalgesia; Mice; Mice, Transgenic; Microglia; Neurons; Neuropeptides; Nociception; Oxidative Stress; Pain; Reactive Oxygen Species; Spinal Cord Dorsal Horn; Ubiquinone

Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans.

Topics: Adaptation, Ocular; Animals; Anti-Anxiety Agents; Anxiety; Brain; Catalase; Chromatography, Liquid; Disease Models, Animal; Exploratory Behavior; Hindlimb Suspension; Hippocampus; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microarray Analysis; Mitochondria; Organophosphorus Compounds; Tandem Mass Spectrometry; Ubiquinone

HMG-CoA reductase inhibitors (statins) and H63D HFE polymorphism may modify amyotrophic lateral sclerosis (ALS). We hypothesized that statins worsen phenotype in ALS mice, dependent on HFE genotype.. Mice harboring SOD1(G93A) heterozygous for H67D Hfe (homologous to human H63D HFE) were administered simvastatin and/or coenzyme Q10, and were allowed to reach end stage. Disease progression was measured by grip strength. A separate group of animals was administered simvastatin and euthanized at the symptomatic 120-day time-point. Mitochondria from gastrocnemius muscle and lumbar spine were analyzed.. Simvastatin and H67D Hfe accelerated disease progression. Simvastatin decreased survival. Coenzyme Q10 did not rescue statin-induced effects. Statins did not alter mitochondrial protein levels.. Statins and Hfe genotype alter disease course in the ALS mouse model. Because the H63D HFE polymorphism is present in 30% of patients with ALS, studying disease progression in patients who receive statins, stratified for HFE genotype, may guide therapy. Muscle Nerve, 2016 Muscle Nerve 54: 284-291, 2016.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Disease Progression; Extremities; Ferritins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mice, Transgenic; Mitochondria; Motor Activity; Muscle Strength; Muscle, Skeletal; ROC Curve; Spinal Cord; Superoxide Dismutase; Ubiquinone

Dominant optic atrophy (DOA) arises from mutations in the OPA1 gene that promotes fusion of the inner mitochondrial membrane and plays a role in maintaining ATP levels. Patients display optic disc pallor, retinal ganglion cell (RGC) loss and bilaterally reduced vision. We report a randomized, placebo-controlled trial of idebenone at 2000 mg/kg/day in 56 Opa1 mutant mice (B6;C3-Opa1(Q285STOP)), with RGC dendropathy and visual loss, and 63 wildtype mice. We assessed cellular responses in the retina, brain and liver and RGC morphology, by diolistic labeling, Sholl analysis and quantification of dendritic morphometric features. Vision was assessed by optokinetic responses. ATP levels were raised by 0.57 nmol/mg (97.73%, p=0.035) in brain from idebenone-treated Opa1 mutant mice, but in the liver there was an 80.35% (p=0.011) increase in oxidative damage. NQO1 expression in Opa1 mutant mice was reduced in the brain (to 30.5%, p=0.002) but not in retina, and neither expression level was induced by idebenone. ON-center RGCs failed to show major recovery, other than improvements in secondary dendritic length (by 53.89%, p=0.052) and dendritic territory (by 2.22 × 10(4) μm(2) or 90.24%, p=0.074). An improvement in optokinetic response was observed (by 12.2 ± 3.2s, p=0.003), but this effect was not sustained over time. OFF-center RGCs from idebenone-treated wildtype mice showed shrinkage in total dendritic length by 2.40 mm (48.05%, p=0.025) and a 47.37% diminished Sholl profile (p=0.029). Visual function in wildtype idebenone-treated mice was impaired (2.9 fewer head turns than placebo, p=0.007). Idebenone appears largely ineffective in protecting Opa1 heterozygous RGCs from dendropathy. The detrimental effect of idebenone in wildtype mice has not been previously observed and raises some concerns.

Topics: Animals; Antioxidants; Blotting, Western; Dendrites; Disease Models, Animal; Female; GTP Phosphohydrolases; Immunohistochemistry; Male; Mice; Mice, Mutant Strains; Optic Atrophy, Autosomal Dominant; Random Allocation; Retinal Ganglion Cells; Ubiquinone; Visual Acuity

Diabetic neuropathic pain is reduced with tight glycemic control. However, strict control increases the risk of hypoglycemic episodes, which are themselves linked to painful neuropathy. This study explored the effects of hypoglycemia-related painful neuropathy. Pretreatment with coenzyme Q10 (CoQ10) was performed to explore the preventive effect of CoQ10 on hypoglycemia-related acute neuropathic pain. Two strains of mice were used and 1 unit/kg of insulin was given to induce hypoglycemia. Mechanical sensitivity of hindpaw withdrawal thresholds was measured using von Frey filaments. Blood glucose levels were clamped at normal levels by joint insulin and glucose injection to test whether insulin itself induced hypersensitivity. Results suggest that the increased mechanical sensitivity after insulin injection is related to decreased blood glucose levels. When blood glucose levels remained at a normal level by the linked administration of insulin and glucose, mice demonstrated no significant change in mechanical sensitivity. Pretreatment with CoQ10 prevented neuropathic pain and the expression of the stress factor c-Fos. These results support the concept that pain in the diabetic scenario can be the result of hypoglycemia and not insulin itself. Additionally, pretreatment with CoQ10 may be a potent preventive method for the development of neuropathic pain.

Topics: Acute Disease; Analgesics; Animals; Biomarkers; Blood Glucose; Disease Models, Animal; Hyperalgesia; Hypoglycemia; Insulin; Mice, Inbred C57BL; Mice, Inbred CBA; Neuralgia; Pain Threshold; Proto-Oncogene Proteins c-fos; Spinal Cord; Time Factors; Ubiquinone

Aspergillus fumigatus is the predominant airborne pathogenic fungus causing invasive aspergillosis in immunocompromised patients. During infection A. fumigatus has to adapt to oxygen-limiting conditions in inflammatory or necrotic tissue. Previously, we identified a mitochondrial protein to be highly up-regulated during hypoxic adaptation. Here, this protein was found to represent the novel oxidoreductase HorA. In Saccharomyces cerevisiae a homologue was shown to play a role in biosynthesis of coenzyme Q. Consistently, reduced coenzyme Q content in the generated ΔhorA mutant indicated a respective function in A. fumigatus. Since coenzyme Q is involved in cellular respiration and maintaining cellular redox homeostasis, the strain ΔhorA displayed an impaired response to both oxidative and reductive stress, a delay in germination and an accumulation of NADH. Moreover, an increased resistance against antifungal drugs was observed. All phenotypes were completely reversed by the addition of the synthetic electron carrier menadione. The deletion strain ΔhorA showed significantly attenuated virulence in two murine infection models of invasive pulmonary aspergillosis. Therefore, the biosynthesis of coenzyme Q and, particularly, the fungal-specific protein HorA play a crucial role in virulence of A. fumigatus. Due to its absence in mammals, HorA might represent a novel therapeutic target against fungal infections.

Topics: Animals; Antifungal Agents; Aspergillus fumigatus; Azoles; Cell Hypoxia; Disease Models, Animal; Female; Fungal Proteins; Gene Deletion; Invasive Pulmonary Aspergillosis; Mice; Oxidoreductases; Ubiquinone; Virulence

There is conflicting clinical evidence whether administration of coenzyme Q10 (CoQ10) improves function following coronary artery bypass graft surgery (CABG). Using a swine model of hibernating myocardium, we tested whether daily CoQ10 would improve contractile function by MRI at 4-week post-CABG. Twelve pigs underwent a thoracotomy and had a constrictor placed on the left anterior descending (LAD). At 12 weeks, they underwent off-pump bypass and received daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo. At 4-week post-CABG, circumferential strain measurements in the hibernating LAD region from placebo and CoQ10 groups were not different and increased to a similar extent with dobutamine (-14.7 ± 0.6 versus -14.8 ± 0.1, respectively (NS)). Post-sacrifice, oxidant stress markers were obtained in the mitochondrial isolates and protein carbonyl in the placebo, and CoQ10 groups were 6.14 ± 0.36 and 5.05 ± 0.32 nmol/mg, respectively (NS). In summary, CoQ10 did not improve contractile reserve or reduce oxidant stress at 4-week post-CABG.

Topics: Animals; Biomarkers; Biomechanical Phenomena; Cardiotonic Agents; Coronary Artery Bypass, Off-Pump; Coronary Artery Disease; Disease Models, Animal; Female; Magnetic Resonance Imaging; Mitochondria, Heart; Myocardial Contraction; Myocardial Stunning; Myocardium; Oxidative Stress; Protein Carbonylation; Recovery of Function; Stress, Mechanical; Sus scrofa; Time Factors; Ubiquinone

Recent clinical trials have shown that in vivo and ex vivo gene therapy strategies can be an option for the treatment of several neurological disorders. Both strategies require efficient and safe vectors to 1) deliver the therapeutic gene directly into the CNS or 2) to genetically modify stem cells that will be used as Trojan horses for the systemic delivery of the therapeutic protein. A group of target diseases for these therapeutic strategies are mitochondrial encephalopathies due to mutations in nuclear DNA genes. In this study, we have developed a lentiviral vector (CCoq9WP) able to overexpress Coq9 mRNA and COQ9 protein in mouse embryonic fibroblasts (MEFs) and hematopoietic progenitor cells (HPCs) from Coq9R239X mice, an animal model of mitochondrial encephalopathy due to primary Coenzyme Q (CoQ) deficiency. Ectopic over-expression of Coq9 in both cell types restored the CoQ biosynthetic pathway and mitochondrial function, improving the fitness of the transduced cells. These results show the potential of the CCoq9WP lentiviral vector as a tool for gene therapy to treat mitochondrial encephalopathies.

Topics: Animals; Bone Marrow Transplantation; Disease Models, Animal; Fibroblasts; Gene Expression; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cells; Lentivirus; Mice; Mice, Knockout; Mitochondria; Mitochondrial Encephalomyopathies; Mitochondrial Proteins; Physical Fitness; Transduction, Genetic; Ubiquinone

Myopathy is among the well documented and the most disturbing adverse effects of statins. The underlying mechanism is still unknown. Mitochondrial dysfunction related to coenzyme Q10 decline is one of the proposed theories. The present study aimed to investigate the mechanism of atorvastatin-induced myopathy in rats. In addition, the mechanism of the coenzyme Q10 protection was investigated with special focus of mitochondrial alterations. Sprague-Dawely rats were treated orally either with atorvastatin (100mg/kg) or atorvastatin and coenzyme Q10 (100mg/kg). Myopathy was assessed by measuring serum creatine kinase (CK) and myoglobin levels together with examination of necrosis in type IIB fiber muscles. Mitochondrial dysfunction was evaluated by measuring muscle lactate/pyruvate ratio, ATP level, pAkt as well as mitochondrial ultrastructure examination. Atorvastatin treatment resulted in a rise in both CK (2X) and myoglobin (6X) level with graded degrees of muscle necrosis. Biochemical determinations showed prominent increase in lactate/pyruvate ratio and a decline in both ATP (>80%) and pAkt (>50%) levels. Ultrastructure examination showed mitochondrial swelling with disrupted organelle membrane. Co-treatment with coenzyme Q10 induced reduction in muscle necrosis as well as in CK and myoglobin levels. In addition, coenzyme Q10 improved all mitochondrial dysfunction parameters including mitochondrial swelling and disruption. These results presented a model for atorvastatin-induced myopathy in rats and proved that mitochondrial dysfunction is the main contributor in statin-myopathy pathophysiology.

Topics: Adenosine Triphosphate; Animals; Atorvastatin; Creatine Kinase; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; L-Lactate Dehydrogenase; Lactic Acid; Male; Microscopy, Electron, Transmission; Mitochondria, Muscle; Motor Activity; Muscle, Skeletal; Muscular Diseases; Myoglobin; Pyruvic Acid; Rats; Rats, Sprague-Dawley; Ubiquinone

The neuroprotective effect of ubiquinone (coenzyme Q10)was demonstrated on the rats model of ischemic stroke provoked by persistent 24-h occlusion of the middle cerebral artery. Coenzyme Q10 (30 mg/kg) was injected intravenously in 60 min after artery occlusion. Ubiquinone crossed the blood-brain barrier, accumulated in the brain, and produced a neuroprotective effect: it alleviated ischemia-induced neurological deficit and reduced the size of necrotic zone by 49% in comparison with rats receiving physiological saline.

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Infarction, Middle Cerebral Artery; Injections, Intravenous; Male; Neuroprotective Agents; Rats, Wistar; Ubiquinone

Does supplementation with co-enzyme Q10 (CoQ10) improve the oocyte mitochondrial abnormalities associated with obesity in mice?. In an obese mouse model, CoQ10 improves the mitochondrial function of oocytes.. Obesity impairs oocyte quality. Oocytes from mice fed a high-fat/high-sugar (HF/HS) diet have abnormalities in mitochondrial distribution and function and in meiotic progression.. Mice were randomly assigned to a normal, chow diet or an isocaloric HF/HS diet for 12 weeks. After 6 weeks on the diet, half of the mice receiving a normal diet and half of the mice receiving a HF/HS diet were randomly assigned to receive CoQ10 supplementation injections for the remaining 6 weeks.. Dietary intervention was initiated on C57Bl6 female mice at 4 weeks of age, CoQ10 versus vehicle injections were assigned at 10 weeks, and assays were conducted at 16 weeks of age. Mice were super-ovulated, and oocytes were collected and stained to assess mitochondrial distribution, quantify reactive oxygen species (ROS), assess meiotic spindle formation, and measure metabolites. In vitro fertilization was performed, and blastocyst embryos were transferred into control mice. Oocyte number, fertilization rate, blastulation rate and implantation rate were compared between the four cohorts. Bivariate statistics were performed appropriately.. HF/HS mice weighed significantly more than normal diet mice (29 versus 22 g, P< 0.001). CoQ10 supplementation did not influence weight. Levels of ATP, citrate, and phosphocreatine were lower and ROS levels were higher in HF/HS mice than in controls (P< 0.001). CoQ10 supplementation significantly increased the levels of metabolites and decreased ROS levels in oocytes from normal diet mice but not in oocytes from HF/HS mice. However, CoQ10 completely prevented the mitochondrial distribution abnormalities observed in the HF/HS mice. Overall, CoQ10 supplementation significantly increased the percentage of normal spindle and chromosome alignment (92.3 versus 80.2%, P= 0.039). In the sub-analysis by diet, the difference did not reach statistical significance. When undergoing IVF, there were no statistically significant differences in the number of mature oocytes, the fertilization rate, blastocyst formation rates, implantation rates, resorption rates or litter size between HF/HS mice receiving CoQ10 or vehicle injections.. Experiments were limited to one species and strain of mice. The majority of experiments were performed after ovulation induction, which may not represent natural cycle fertility.. Improvement in oocyte mitochondrial distribution and function of normal, chow-fed mice and HF/HS-fed mice demonstrates the importance of CoQ10 and the efficiency of the mitochondrial respiratory chain in oocyte competence. Clinical studies are now needed to evaluate the therapeutic potential of CoQ10 in women's reproductive health.. C.E.B. received support from the National Research Training Program in Reproductive Medicine sponsored by the National Institute of Health (T32 HD040135-13) and the Scientific Advisory Board of Vivere Health. K.H.M received support from the American Diabetes Association and the National Institute of Health (R01 HD083895). There are no conflicts of interest to declare.. This study is not a clinical trial.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Female; Mice; Mitochondria; Obesity; Oocytes; Reactive Oxygen Species; Treatment Outcome; Ubiquinone

Considerable evidence demonstrated that the central role of reactive oxygen species and reactive nitrogen species (ROS and RNS) in the development of thermal hyperalgesia is associated to acute and chronic inflammation. Idebenone (IDE), a synthetic analogue of the endogenous cellular antioxidant coenzyme Q10 (CoQ10), is an active drug in the central nervous system which shows a protection in a variety of neurological disorders. Since it is lipophilic, poorly water soluble and highly bound to plasma proteins, different technological approaches have been explored to increase its solubility and new pharmaceutical properties. Therefore, it has been complexed with HP-β-cyclodextrins (HP) and its efficacy has been assessed in an animal model of carrageenan-induced thermal hyperalgesia. All male rats used for this study received a subplantar injection of carrageenan into the right hindpaw in the presence or absence of IDE alone and IDE/HP complex. We observed that IDE poorly reduced painful carrageenan effects whereas IDE/HP complex was able to prevent carrageenan-induced hyperalgesia and edema in a dose-dependent manner, reducing spinal MDA levels and protein nitration. Hence, our results demonstrated that when complexed with HP, idebenone exerts a potent analgesic and anti-inflammatory efficacy.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Compounding; Edema; Hyperalgesia; Inflammation; Male; Malondialdehyde; Oxidative Stress; Rats, Sprague-Dawley; Spinal Cord; Superoxide Dismutase; Time Factors; Ubiquinone

The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease.

Topics: Animals; Behavior, Animal; Cerebellar Ataxia; Cerebellum; Chlorocebus aethiops; COS Cells; Disease Models, Animal; Exercise Tolerance; Female; Genetic Predisposition to Disease; HEK293 Cells; Humans; Lipid Metabolism; Male; Maze Learning; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Models, Molecular; Motor Activity; Muscle Strength; Muscle, Skeletal; Phenotype; Protein Binding; Protein Conformation; Proteomics; Recognition, Psychology; Rotarod Performance Test; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Seizures; Structure-Activity Relationship; Time Factors; Transfection; Ubiquinone

Neuropathic pain is a common side-effect of chemotherapy. Although precise mechanisms are unclear, oxidative stress and mitochondrial damage are involved. We investigated whether the mitochondria targeted antioxidant, MitoVitE, provided better protection against paclitaxel-induced mitochondrial damage in rat dorsal root ganglion (DRG) cells, than a non-targeted form of vitamin E, Trolox. We also determined whether MitoVitE, compared with duloxetine, could limit paclitaxel-induced mechanical hypersensitivity in rats.. Mitochondrial function was measured in DRG cells exposed to paclitaxel with and without MitoVitE or Trolox. The effect of MitoVitE or Trolox on paclitaxel-induced cell killing in cancer cell lines was also determined. Rats received a cumulative dose of 8 mg kg. Paclitaxel caused loss of membrane potential in DRG cells. At 100 µM paclitaxel median [range] change was 61[44-78]%, P < 0.0001, which was ameliorated by MitoVitE (86[62-104]%) but not Trolox (46[46-57]%). Similarly, loss of metabolic activity and glutathione induced by paclitaxel (both P < 0.0001) were reduced by MitoVitE but not Trolox. Cytotoxicity of paclitaxel was not affected by co-exposure of ovarian cancer cells to either MitoVitE or Trolox, but was slightly reduced against breast cancer cells, in the presence of Trolox. Mean (SD) areas under the curve of withdrawal thresholds at 6 h after injection in rats given paclitaxel + control, or + MitoVitE (P < 0.0001) or + duloxetine (P < 0.0001) were 110 (5), 145 (10) and 156 (13) respectively.. Paclitaxel affected mitochondrial function and glutathione in DRG cells, which was abrogated by MitoVitE but not Trolox, without decreasing cancer cell cytotoxicity. In rats, paclitaxel-induced mechanical hypersensitivity was ameliorated by MitoVitE treatment to an extent similar to duloxetine. These data confirm mitochondria as a mechanistic target for paclitaxel-induced damage and suggest mitochondria targeted antioxidants as future therapeutic strategies.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Disease Models, Animal; Hyperalgesia; In Vitro Techniques; Male; Mitochondria; Neuralgia; Organophosphorus Compounds; Oxidative Stress; Paclitaxel; Rats; Rats, Sprague-Dawley; Ubiquinone

Myelodysplastic syndromes (MDS) are hallmarked by cytopenia and dysplasia of hematopoietic cells, often accompanied by mitochondrial dysfunction and increases of reactive oxygen species (ROS) within affected cells. However, it is not known whether the increase in ROS production is an instigator or a byproduct of the disease. The present investigation shows that mice lacking immediate early responsive gene X-1 (IEX-1) exhibit lineage specific increases in ROS production and abnormal cytology upon radiation in blood cell types commonly identified in MDS. These affected cell lineages chiefly have the bone marrow as a primary site of differentiation and maturation, while cells with extramedullary differentiation and maturation like B- and T-cells remain unaffected. Increased ROS production is likely to contribute significantly to irradiation-induced thrombocytopenia in the absence of IEX-1 as demonstrated by effective reversal of the disorder after mitoquinone (MitoQ) treatment, a mitochondria-specific antioxidant. MitoQ reduced intracellular ROS production within megakaryocytes and platelets. It also normalized mitochondrial membrane potential and superoxide production in platelets in irradiated, IEX-1 deficient mice. The lineage-specific effects of mitochondrial ROS may help us understand the etiology of thrombocytopenia in association with MDS in a subgroup of the patients.

Topics: Animals; Antioxidants; Blood Platelets; Bone Marrow; Cell Lineage; Disease Models, Animal; Immediate-Early Proteins; Megakaryocytes; Membrane Potential, Mitochondrial; Mice; Mice, Knockout; Mitochondria; Organophosphorus Compounds; Reactive Oxygen Species; Superoxides; Thrombocytopenia; Thrombopoiesis; Ubiquinone; Whole-Body Irradiation

This study investigates the effect of insulin combined with idebenone on blood-brain barrier (BBB) permeability in experimental streptozotocin-induced diabetic rats as well as the underlying mechanisms. With a diabetic rat model, we show that insulin and idebenone normalize body weight and water intake and restore BBB permeability and that their combination displays a synergistic effect. The results from transmission electron microscopy show that the combination of insulin and idebenone significantly closed the tight junction (TJ) in diabetic rats. The results from Western blotting in diabetic rats show that the upregulation of TJ-associated proteins occludin, and zonula occludens (ZO)-1 caused by the combination of insulin and idebenone is more remarkable than that with either agent alone. In addition, the activations of reactive oxygen species (ROS) and advanced glycation end products (AGEs) and the expression levels of receptors for advanced glycation end-products (RAGE) and nuclear factor-κB (NF-κB) were significantly decreased after treatment with insulin and idebenone in diabetic rats. These results suggest that the combination of insulin and idebenone could decrease the BBB permeability in diabetic rats by upregulating the expression of occludin, claudin-5, and ZO-1 and that the ROS/AGE/RAGE/NF-κB signal pathway might be involved in the process.

Topics: Animals; Antioxidants; Blood-Brain Barrier; Capillary Permeability; Diabetes Mellitus, Experimental; Disease Models, Animal; Hypoglycemic Agents; Insulin; Male; Microscopy, Electron, Transmission; Nucleoproteins; Rats; Rats, Wistar; Reactive Oxygen Species; Statistics, Nonparametric; Ubiquinone

Left ventricular (LV) volume overload (VO) results in cardiomyocyte oxidative stress and mitochondrial dysfunction. Because mitochondria are both a source and target of ROS, we hypothesized that the mitochondrially targeted antioxidant mitoubiquinone (MitoQ) will improve cardiomyocyte damage and LV dysfunction in VO. Isolated cardiomyocytes from Sprague-Dawley rats were exposed to stretch in vitro and VO of aortocaval fistula (ACF) in vivo. ACF rats were treated with and without MitoQ. Isolated cardiomyocytes were analyzed after 3 h of cyclical stretch or 8 wk of ACF with MitoSox red or 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate to measure ROS and with tetramethylrhodamine to measure mitochondrial membrane potential. Transmission electron microscopy and immunohistochemistry were used for cardiomyocyte structural assessment. In vitro cyclical stretch and 8-wk ACF resulted in increased cardiomyocyte mitochondrial ROS production and decreased mitochondrial membrane potential, which were significantly improved by MitoQ. ACF had extensive loss of desmin and β₂-tubulin that was paralleled by mitochondrial disorganization, loss of cristae, swelling, and clustering identified by mitochondria complex IV staining and transmission electron microscopy. MitoQ improved mitochondrial structural damage and attenuated desmin loss/degradation evidenced by immunohistochemistry and protein expression. However, LV dilatation and fractional shortening were unaffected by MitoQ treatment in 8-wk ACF. In conclusion, although MitoQ did not affect LV dilatation or function in ACF, these experiments suggest a connection of cardiomyocyte mitochondria-derived ROS production with cytoskeletal disruption and mitochondrial damage in the VO of ACF.

Topics: Animals; Antioxidants; Cytoskeleton; Desmin; Disease Models, Animal; Heart Failure; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; Rats, Sprague-Dawley; Reactive Oxygen Species; Time Factors; Tubulin; Ubiquinone; Ventricular Dysfunction, Left; Ventricular Function, Left

Spinal cord ischemia remains a serious complication of thoracoabdominal aortic aneurysm surgery. Coenzyme Q10, a potent antioxidant, has been reported to exert a neuroprotective effect. In the present study, we evaluated the effect of coenzyme Q10 pretreatment on spinal cord ischemia-reperfusion injury.. Male Sprague-Dawley rats were treated with either 300 mg/kg coenzyme Q10 (CoQ10 group, n = 12) or saline (control and sham groups, n = 12 for each group) for 5 days before ischemia. Spinal cord ischemia was induced in the control and CoQ10 groups. Neurological function was assessed using the Basso-Beattie-Bresnahan (BBB) motor rating scale until 7 days after reperfusion, and then the spinal cord was harvested for histopathological examinations and an evaluation of malondialdehyde level.. On post-reperfusion Day 1, the CoQ10 group showed higher BBB scores compared with those in the control group, although the difference was not significant. However, on Day 2, the CoQ10 group showed a significantly higher BBB score than the control group (14.0 [10.3-15.0] vs 8.0 [5.0-9.8], median [IQR], respectively; p = 0.021), and this trend was maintained until Day 7 (17.5 [16.0-18.0] vs 9.0 [6.5-12.8], respectively; p < 0.001). Compared with the control group, the CoQ10 group had more normal motor neurons (p = 0.003), fewer apoptotic changes (p = 0.003) and a lower level of tissue malondialdehyde (p = 0.024).. Pretreatment with 300 mg/kg coenzyme Q10 resulted in significantly improved neurological function and preservation of more normal motor neurons.

Topics: Animals; Disease Models, Animal; Neurologic Examination; Premedication; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Spinal Cord; Ubiquinone

Genetic defects in the UBE3A gene, which encodes for the imprinted E6-AP ubiquitin E3 ligase (UBE3A), is responsible for the occurrence of Angelman syndrome (AS), a neurodegenerative disorder which arises in 1 out of every 12,000-20,000 births. Classical symptoms of AS include delayed development, impaired speech, and epileptic seizures with characteristic electroencephalography (EEG) readings. We have previously reported impaired mitochondrial structure and reduced complex III in the hippocampus and cerebellum in the Ube3a(m-/p+) mice. CoQ10 supplementation restores the electron flow to the mitochondrial respiratory chain (MRC) to ultimately increase mitochondrial antioxidant capacity. A number of recent studies with CoQ10 analogues seem promising in providing therapeutic benefit to patients with a variety of disorders. CoQ10 therapy has been reported to be safe and relatively well-tolerated at doses as high as 3000mg/day in patients with disorders of CoQ10 biosynthesis and MRC disorders. Herein, we report administration of idebenone, a potent CoQ10 analogue, to the Ube3a(m-/p+) mouse model corrects motor coordination and anxiety levels, and also improves the expression of complexes III and IV in hippocampus CA1 and CA2 neurons and cerebellum in these Ube3a(m-/p+) mice. However, treatment with idebenone illustrated no beneficial effects in the reduction of oxidative stress. To our knowledge, this is the first study to suggest an improvement in mitochondrial respiratory chain dysfunction via bioenergetics modulation with a CoQ10 analogue. These findings may further elucidate possible cellular and molecular mechanism(s) and ultimately a clinical therapeutic approach/benefit for patients with Angelman syndrome.

Topics: Angelman Syndrome; Animals; Antioxidants; Cerebellum; Disease Models, Animal; Electron Transport; Hippocampus; Mice; Mitochondria; Motor Activity; Oxidative Stress; Ubiquinone; Ubiquitin-Protein Ligases

Cystinosis is an inherited disorder resulting from a mutation in the CTNS gene, causing progressive proximal tubular cell flattening, the so-called swan-neck lesion (SNL), and eventual renal failure. To determine the role of oxidative stress in cystinosis, histologic sections of kidneys from C57BL/6 Ctns(-/-) and wild-type mice were examined by immunohistochemistry and morphometry from 1 wk to 20 mo of age. Additional mice were treated from 1 to 6 mo with vehicle or mitoquinone (MitoQ), an antioxidant targeted to mitochondria. The leading edge of the SNL lost mitochondria and superoxide production, and became surrounded by a thickened tubular basement membrane. Progression of the SNL as determined by staining with lectin from Lotus tetragonolobus accelerated after 3 mo, but was delayed by treatment with MitoQ (38 ± 4% vs. 28 ± 1%, P < 0.01). Through 9 mo, glomeruli had retained renin staining and intact macula densa, whereas SNL expressed transgelin, an actin-binding protein, but neither kidney injury molecule-1 (KIM-1) nor cell death was observed. After 9 mo, clusters of proximal tubules exhibited localized oxidative stress (4-hydroxynonenal binding), expressed KIM-1, and underwent apoptosis, leading to the formation of atubular glomeruli and accumulation of interstitial collagen. We conclude that nephron integrity is initially maintained in the Ctns(-/-) mouse by adaptive flattening of cells of the SNL through loss of mitochondria, upregulation of transgelin, and thickened basement membrane. This adaptation ultimately fails in adulthood, with proximal tubular disruption, formation of atubular glomeruli, and renal failure. Antioxidant treatment targeted to mitochondria delays initiation of the SNL, and may provide therapeutic benefit in children with cystinosis.

Topics: Adaptation, Physiological; Amino Acid Transport Systems, Neutral; Animals; Antioxidants; Apoptosis; Cystinosis; Disease Models, Animal; Female; Hepatitis A Virus Cellular Receptor 1; Kidney Tubules, Proximal; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mutation; Organophosphorus Compounds; Oxidative Stress; Superoxides; Ubiquinone

The aim of study was to search for new biomarkers with a magnetic resonance technique to identify the early stages of dementia, induced by D-galactose, and evaluate Simvastatin therapy. Localized proton magnetic resonance spectroscopy measurements showed a significant decrease in the concentration of N-acetylaspartate+N-acetylaspartylglutamate and myo-inositol in the D-galactose group compared to the control group, and, conversely, an increase of N-acetylaspartate+N-acetylaspartylglutamate in the D-galactose/Simvastatin group. Using a saturation transfer experiment, with phosphorus magnetic resonance spectroscopy, we observed a significant elevation of the forward rate constant of the creatine kinase reaction in the brains of the D-galactose group compared to controls, and subsequently, a significant reduction of this reaction in the D-galactose/Simvastatin group. Spatial learning and memory were evaluated using the modified Morris water maze test. The dynamics of the learning process represented by the learning index revealed a significant reduction in learning in the D-galactose group, but the deficits as a consequence of the D-galactose effects were recovered in the D-galactose/Simvastatin group, in which the learning dynamics resembled those of the control group. By determining the thiobarbituric acid reactive substances and total coenzyme Q9 in plasma, we have shown that long-term administration of D-galactose created conditions for oxidative stress, and that the administration of Simvastatin decreased oxidative stress in plasma. Volumetry analyses from the hippocampal area show a reduction in the segmented area in the D-galactose group, compared with the control group, and an enlarged area in the hippocampus in the d-galactose/Simvastatin group.

Topics: Animals; Aspartic Acid; Biomarkers; Brain; Dementia; Dipeptides; Disease Models, Animal; Galactose; Inositol; Magnetic Resonance Spectroscopy; Male; Nootropic Agents; Organ Size; Phosphorus Isotopes; Protons; Rats, Wistar; Simvastatin; Spatial Learning; Spatial Memory; Thiobarbituric Acid Reactive Substances; Treatment Outcome; Ubiquinone

Ulcerative colitis is a chronic inflammatory bowel disease. Recent studies reported a pivotal role of elevated intracellular calcium in this disorder. Coenzyme Q10 (CoQ10) and amlodipine are known to maintain cellular energy, decrease intracellular calcium concentration in addition to their antioxidant and anti-inflammatory properties.. The aim of this study was to evaluate the possible protective effects of CoQ10, amlodipine and their combination on ulcerative colitis.. Colitis was induced in rats by intracolonic injection of 3% acetic acid. CoQ10 (10 mg/kg), amlodipine (3 mg/kg) and their combination were administered for 8 consecutive days before induction of colitis.. Our results showed that administration of CoQ10, amlodipine and their combination decreased colon tissue malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), prostaglandin E2 (PGE2), myeloperoxidase (MPO) and heat shock protein (HSP70) levels induced by intracolonic injection of acetic acid and restored many of the colon structure in histological examination. On the other hand, they increased superoxide dismutase (SOD) activity, adenosine-5'-triphosphate (ATP) and interleukin-10 (IL-10) colonic contents.. Administration of either CoQ10 or amlodipine was found to protect against acetic acid-induced colitis. Moreover, their combination was more effective than individual administration of either of them. The protective effect of CoQ10 and amlodipine may be in part via their antioxidant, anti-inflammatory and energy restoration properties.

Topics: Amlodipine; Animals; Anti-Inflammatory Agents; Antioxidants; Colitis, Ulcerative; Colon; Dinoprostone; Disease Models, Animal; Energy Metabolism; Interleukin-1beta; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Ubiquinone

Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype-phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9(Q95X) and Coq9(R239X)), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9(R239X) mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. In contrast, Coq9(Q95X) mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9(R239X) mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype-phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.

Topics: Animals; Ataxia; Disease Models, Animal; Genetic Variation; Genotype; Hydroxybenzoates; Mammals; Mice; Mice, Transgenic; Mitochondrial Diseases; Muscle Weakness; Mutation, Missense; Ubiquinone

Although oxidative stress has been strongly implicated in the development of acute pancreatitis (AP), antioxidant therapy in patients has so far been discouraging. The aim of this study was to assess potential protective effects of a mitochondria-targeted antioxidant, MitoQ, in experimental AP using in vitro and in vivo approaches. MitoQ blocked H2O2-induced intracellular ROS responses in murine pancreatic acinar cells, an action not shared by the control analogue dTPP. MitoQ did not reduce mitochondrial depolarisation induced by either cholecystokinin (CCK) or bile acid TLCS, and at 10 µM caused depolarisation per se. Both MitoQ and dTPP increased basal and CCK-induced cell death in a plate-reader assay. In a TLCS-induced AP model MitoQ treatment was not protective. In AP induced by caerulein hyperstimulation (CER-AP), MitoQ exerted mixed effects. Thus, partial amelioration of histopathology scores was observed, actions shared by dTPP, but without reduction of the biochemical markers pancreatic trypsin or serum amylase. Interestingly, lung myeloperoxidase and interleukin-6 were concurrently increased by MitoQ in CER-AP. MitoQ caused biphasic effects on ROS production in isolated polymorphonuclear leukocytes, inhibiting an acute increase but elevating later levels. Our results suggest that MitoQ would be inappropriate for AP therapy, consistent with prior antioxidant evaluations in this disease.

Topics: Acinar Cells; Acute Disease; Animals; Antioxidants; Apoptosis; Ceruletide; Cholecystokinin; Disease Models, Animal; Inflammation; Male; Membrane Potential, Mitochondrial; Mice; Mitochondria; Necrosis; Organophosphorus Compounds; Oxidative Stress; Pancreas; Pancreatitis; Reactive Oxygen Species; Taurolithocholic Acid; Ubiquinone

Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failure. We previously demonstrated that LV phosphoinositide 3-kinase p110α (PI3K) protects the heart against diabetic cardiomyopathy, associated with reduced NADPH oxidase expression and activity. Conversely, in dominant negative PI3K(p110α) transgenic mice (dnPI3K), reduced cardiac PI3K signaling exaggerated diabetes-induced cardiomyopathy, associated with upregulated NADPH oxidase. The goal was to examine whether chronic supplementation with the antioxidant coenzyme Q(10) (CoQ(10)) could attenuate LV superoxide and diabetic cardiomyopathy in a setting of impaired PI3K signaling. Diabetes was induced in 6-week-old nontransgenic and dnPI3K male mice via streptozotocin. After 4 weeks of diabetes, CoQ(10) supplementation commenced (10 mg/kg ip, 3 times/week, 8 weeks). At study end (12 weeks of diabetes), markers of LV function, cardiomyocyte hypertrophy, collagen deposition, NADPH oxidase, oxidative stress (3-nitrotyrosine), and concentrations of CoQ(9) and CoQ(10) were determined. LV NADPH oxidase (Nox2 gene expression and activity, and lucigenin-enhanced chemiluminescence), as well as oxidative stress, were increased by diabetes, exaggerated in diabetic dnPI3K mice, and attenuated by CoQ(10). Diabetes-induced LV diastolic dysfunction (prolonged deceleration time, elevated end-diastolic pressure, impaired E/A ratio), cardiomyocyte hypertrophy and fibrosis, expression of atrial natriuretic peptide, connective tissue growth factor, and β-myosin heavy chain were all attenuated by CoQ(10). Chronic CoQ(10) supplementation attenuates aspects of diabetic cardiomyopathy, even in a setting of reduced cardiac PI3K protective signaling. Given that CoQ(10) supplementation has been suggested to have positive outcomes in heart failure patients, chronic CoQ(10) supplementation may be an attractive adjunct therapy for diabetic heart failure.

Topics: Animals; Antioxidants; Class I Phosphatidylinositol 3-Kinases; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Humans; Male; Mice; Mice, Transgenic; NADPH Oxidases; Oxidative Stress; Phosphatidylinositol 3-Kinases; Signal Transduction; Ubiquinone; Ventricular Dysfunction, Left

Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant synthesized in human body. This enzyme promotes immune system function and can be used as a dietary supplement. Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. RA results in severe destruction of cartilage and disability. This study aimed to investigate the effect of CoQ10 on inflammation and Th17 cell proliferation on an experimental rheumatoid arthritis (RA) mice model. CoQ10 or cotton seed oil as control was orally administrated once a day for seven weeks to mice with zymosan-induced arthritis (ZIA). Histological analysis of the joints was conducted using immunohistochemistry. Germinal center (GC) B cells, Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. mRNA expression was measured by real-time PCR and protein levels were estimated by enzyme-linked immunosorbent assay (ELISA). Flow cytometric analysis (FACS) was used to evaluate Th17 cells and Treg cells. CoQ10 mitigated the severity of ZIA and decreased serum immunoglobulin concentrations. CoQ10 also reduced RANKL-induced osteoclastogenesis, inflammatory mediators and oxidant factors. Th17/Treg axis was reciprocally controlled by CoQ10 treatment. Moreover, CoQ10 treatment on normal mouse and human cells cultured in Th17 conditions decreased the number of Th17 cells and enhanced the number of Treg cells. CoQ10 alleviates arthritis in mice with ZIA declining inflammation, Th17 cells and osteoclast differentiation. These findings suggest that CoQ10 can be a potential therapeutic substance for RA.

Topics: Animals; Arthritis, Experimental; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Bone Resorption; Cell Differentiation; Disease Models, Animal; Germinal Center; Humans; Immunophenotyping; Immunosuppressive Agents; Interleukin-17; Leukocytes, Mononuclear; Mice; Osteoclasts; Spleen; T-Lymphocyte Subsets; Th17 Cells; Ubiquinone; Zymosan

Topics: Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Organophosphorus Compounds; Oxidative Stress; Ubiquinone

Free radical production and mitochondrial dysfunction during cardiac graft reperfusion is a major factor in post-transplant ischemia-reperfusion (IR) injury, an important underlying cause of primary graft dysfunction. We therefore assessed the efficacy of the mitochondria-targeted anti-oxidant MitoQ in reducing IR injury in a murine heterotopic cardiac transplant model.. Hearts from C57BL/6 donor mice were flushed with storage solution alone, solution containing the anti-oxidant MitoQ, or solution containing the non-anti-oxidant decyltriphenylphosphonium control and exposed to short (30 minutes) or prolonged (4 hour) cold preservation before transplantation. Grafts were transplanted into C57BL/6 recipients and analyzed for mitochondrial reactive oxygen species production, oxidative damage, serum troponin, beating score, and inflammatory markers 120 minutes or 24 hours post-transplant.. MitoQ was taken up by the heart during cold storage. Prolonged cold preservation of donor hearts before IR increased IR injury (troponin I, beating score) and mitochondrial reactive oxygen species, mitochondrial DNA damage, protein carbonyls, and pro-inflammatory cytokine release 24 hours after transplant. Administration of MitoQ to the donor heart in the storage solution protected against this IR injury by blocking graft oxidative damage and dampening the early pro-inflammatory response in the recipient.. IR after heart transplantation results in mitochondrial oxidative damage that is potentiated by cold ischemia. Supplementing donor graft perfusion with the anti-oxidant MitoQ before transplantation should be studied further to reduce IR-related free radical production, the innate immune response to IR injury, and subsequent donor cardiac injury.

Topics: Animals; Antioxidants; Disease Models, Animal; Female; Free Radical Scavengers; Heart Transplantation; Male; Mice; Mice, Inbred C57BL; Micronutrients; Mitochondria, Heart; Organ Preservation; Organophosphorus Compounds; Oxidative Stress; Primary Graft Dysfunction; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Ubiquinone

Cardioprotective efficacy of coenzyme Q10 (CoQ10, ubidecarenone) and mexicor were evaluated on the 21st day of experimental myocardial infarction in Wistar rats. CoQ10 or mexicor were injected in a dose of 30 mg/kg intravenously 10 min after coronary artery occlusion. The observed cardioprotective effects of ubidecarenone and mexicor were close. Both drugs equally increased the survival of rats, prevented the development of dilatation and hypertrophy of the left ventricle, and improved the pump cardiac function.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Male; Myocardial Infarction; Pyridines; Rats; Rats, Wistar; Ubiquinone; Vitamins

Obesity is a major risk factor for the onset of type 2 diabetes; however, little is known about the gene(s) involved. Therefore, we developed new animal models of obesity to search for diabetogenic genes associated with obesity. We generated double congenic rat strains with a hyperglycaemic quantitative trait locus (QTL) derived from the Otsuka Long-Evans Tokushima Fatty rat and a fa/fa (Lepr-/-) locus derived from the Zucker Fatty rat; phenotypic analysis for plasma glucose and insulin levels and RNA and protein levels were determined using reverse transcription quantitative PCR and Western blotting analyses, respectively. The double congenic strain F344-fa-nidd2 (Lepr-/- and Nidd2/of) exhibited significantly higher glucose levels and significantly lower hypoglycaemic response to insulin than the obese control strain F344-fa (Lepr-/-). These phenotypes were clearly observed in the obese strains but not in the lean strains. These results indicate that the Nidd2/of locus harbours a diabetogenic gene associated with obesity. We measured the expression of 60 genes in the Nidd2/of QTL region between the strains and found that the mRNA expression levels of five genes were significantly different between the strains under the condition of obesity. However, three of the five genes were differentially expressed in both obese and lean rats, indicating that these genes are not specific for the condition of obesity. Conversely, the other two genes, coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8), were differentially expressed only in the obese rats, suggesting that these two genes are candidates for the onset of type 2 diabetes associated with obesity in rats.

Topics: Animals; Base Sequence; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression; Genetic Association Studies; Genetic Predisposition to Disease; Liver; Male; Obesity; Pregnancy Proteins; Quantitative Trait Loci; Rats, Inbred F344; Sequence Analysis, DNA; Ubiquinone

Alzheimer's disease (AD) is the most common form of dementia. The deposition of brain amyloid-β peptides (Aβ), which are cleaved from amyloid precursor protein (APP), is one of the pathological hallmarks of AD. Aβ-induced oxidative stress and neuroinflammation play important roles in the pathogenesis of AD. Antroquinonol, a ubiquinone derivative isolated from Antrodia camphorata, has been shown to reduce oxidative stress and inflammatory cytokines via activating the nuclear transcription factor erythroid-2-related factor 2 (Nrf2) pathway, which is downregulated in AD. Therefore, we examined whether antroquinonol could improve AD-like pathological and behavioral deficits in the APP transgenic mouse model. We found that antroquinonol was able to cross the blood-brain barrier and had no adverse effects via oral intake. Two months of antroquinonol consumption improved learning and memory in the Morris water maze test, reduced hippocampal Aβ levels, and reduced the degree of astrogliosis. These effects may be mediated through the increase of Nrf2 and the decrease of histone deacetylase 2 (HDAC2) levels. These findings suggest that antroquinonol could have beneficial effects on AD-like deficits in APP transgenic mouse.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Blood-Brain Barrier; Disease Models, Animal; Hippocampus; Histone Deacetylase 2; Mice; Mice, Transgenic; NF-E2-Related Factor 2; Rats; Spatial Learning; Spatial Memory; Ubiquinone

Citrobacter rodentium is a murine pathogen that serves as a model for enteropathogenic Escherichia coli. C. rodentium infection reduced the quantity and activity of mitochondrial respiratory complexes I and IV, as well as phosphorylation capacity, mitochondrial transmembrane potential and ATP generation at day 10, 14 and 19 post infection. Cytokine mRNA quantification showed increased levels of IFNγ, TNFα, IL-4, IL-6, and IL-12 during infection. The effects of adding these cytokines, C. rodentium and E. coli were hence elucidated using an in vitro colonic mucosa. Both infection and TNFα, individually and combined with IFNγ, decreased complex I and IV enzyme levels and mitochondrial function. However, IL-4 reversed these effects, and IL-6 protected against loss of complex IV. Both in vivo and in vitro, the dysfunction appeared caused by nitric oxide-generation, and was alleviated by an antioxidant targeting mitochondria. IFNγ -/- mice, containing a similar pathogen burden but higher IL-4 and IL-6, displayed no loss of any of the four complexes. Thus, the cytokine environment appears to be a more important determinant of mitochondrial function than direct actions of the pathogen. As IFNγ and TNFα levels increase during clearance of infection, the concomitant increase in IL-4 and IL-6 protects mitochondrial function.

Topics: Adenosine Triphosphate; Animals; Caspase 3; Cell Death; Citrobacter rodentium; Colitis; Cytokines; Disease Models, Animal; Electron Transport Chain Complex Proteins; Enterobacteriaceae Infections; Enzyme Activation; Escherichia coli; Interferon-gamma; Interleukin-4; Membrane Potential, Mitochondrial; Mice; Mice, Knockout; Mitochondria; Nitric Oxide; Organophosphorus Compounds; Phosphorylation; Tumor Necrosis Factor-alpha; Ubiquinone

Angelman syndrome (AS) is a neurodevelopmental disorder associated with developmental delay, lack of speech, motor dysfunction, and epilepsy. In the majority of the patients, AS is caused by the deletion of small portions of maternal chromosome 15 harboring the UBE3A gene. This results in a lack of expression of the UBE3A gene because the paternal allele is genetically imprinted. The UBE3A gene encodes an enzyme termed ubiquitin ligase E3A (E6-AP) that targets proteins for degradation by the 26S proteasome. Because neurodegenerative disease and other neurodevelopmental disorders have been linked to oxidative stress, we asked whether mitochondrial reactive oxygen species (ROS) played a role in impaired synaptic plasticity and memory deficits exhibited by AS model mice. We discovered that AS mice have increased levels of superoxide in area CA1 of the hippocampus that is reduced by MitoQ 10-methanesuflonate (MitoQ), a mitochondria-specific antioxidant. In addition, we found that MitoQ rescued impairments in hippocampal synaptic plasticity and deficits in contextual fear memory exhibited by AS model mice. Our findings suggest that mitochondria-derived oxidative stress contributes to hippocampal pathophysiology in AS model mice and that targeting mitochondrial ROS pharmacologically could benefit individuals with AS.. Oxidative stress has been hypothesized to contribute to the pathophysiology of neurodevelopmental disorders, including autism spectrum disorders and Angelman syndrome (AS). Herein, we report that AS model mice exhibit elevated levels of mitochondria-derived reactive oxygen species in pyramidal neurons in hippocampal area CA1. Moreover, we demonstrate that the administration of MitoQ (MitoQ 10-methanesuflonate), a mitochondria-specific antioxidant, to AS model mice normalizes synaptic plasticity and restores memory. Finally, our findings suggest that antioxidants that target the mitochondria could be used therapeutically to ameliorate synaptic and cognitive deficits in individuals with AS.

Topics: Analysis of Variance; Angelman Syndrome; Animals; Conditioning, Psychological; Disease Models, Animal; Electric Stimulation; Fear; Hippocampus; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mitochondria; Motor Activity; Movement Disorders; Organophosphorus Compounds; Superoxides; Synapses; Ubiquinone

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by diminished cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. 7-Dehydrocholesterol is highly reactive, giving rise to biologically active oxysterols.. 7-DHC-derived oxysterols were measured in fibroblasts from SLOS patients and an in vivo SLOS rodent model using high-performance liquid chromatography tandem mass spectrometry. Expression of lipid biosynthesis genes was ascertained by quantitative polymerase chain reaction and Western blot. The effects of an antioxidant mixture of vitamin A, coenzyme Q10, vitamin C, and vitamin E were evaluated for their potential to reduce formation of 7-DHC oxysterols in fibroblast from SLOS patients. Finally, the effect of maternal feeding of vitamin E enriched diet was ascertained in the brain and liver of newborn SLOS mice.. In cultured human SLOS fibroblasts, the antioxidant mixture led to decreased levels of the 7-DHC-derived oxysterol, 3β,5α-dihydroxycholest-7-en-6-one. Furthermore, gene expression changes in SLOS human fibroblasts were normalized with antioxidant treatment. The active ingredient appeared to be vitamin E, as even at low concentrations, it significantly decreased 3β,5α-dihydroxycholest-7-en-6-one levels. In addition, analyzing a mouse SLOS model revealed that feeding a vitamin E enriched diet to pregnant female mice led to a decrease in oxysterol formation in brain and liver tissues of the newborn Dhcr7-knockout pups.. Considering the adverse effects of 7-DHC-derived oxysterols in neuronal and glial cultures and the positive effects of antioxidants in patient cell cultures and the transgenic mouse model, we believe that preventing formation of 7-DHC oxysterols is critical for countering the detrimental effects of DHCR7 mutations.

Topics: alpha-Tocopherol; Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Brain; Cell Line, Transformed; Disease Models, Animal; Female; Fibroblasts; Gene Expression Regulation; Humans; Liver; Male; Mice; Mice, Transgenic; Oxidoreductases Acting on CH-CH Group Donors; Smith-Lemli-Opitz Syndrome; Ubiquinone

Friedreich's ataxia (FRDA), the most common hereditary ataxia, is characterized by progressive degeneration of the central and peripheral nervous system, hypertrophic cardiomyopathy and a high risk of diabetes. FRDA is caused by abnormally low levels of frataxin, a highly conserved mitochondrial protein. Drosophila has been previously successfully used to model FRDA in various cell types, including neurons and glial cells. Here, we report the development of a Drosophila cardiac model of FRDA. In vivo heart imaging revealed profound impairments in heart function in frataxin-depleted Drosophila, including a strong increase in end-systolic and end-diastolic diameters and a decrease in fractional shortening (FS). These features, reminiscent of pathological phenotypes in humans, are fully rescued by complementation with human frataxin, suggesting conserved cardiac functions of frataxin between the two organisms. Oxidative stress is not a major factor of heart impairment in frataxin-depleted flies, suggesting the involvement of other pathological mechanisms notably mitochondrial respiratory chain (MRC) dysfunction. Accordingly, we report that methylene blue (MB), a compound known to act as an alternative electron carrier that bypasses mitochondrial complexes I-III, was able to prevent heart dysfunction. MB also partially rescued the phenotype when administered post-symptomatically. Analysis of MB derivatives demonstrates that only compounds with electron carrier properties are able to prevent the heart phenotype. Thus MB, a compound already used for several clinical applications, appears promising for the treatment of the heart dysfunctions that are a major cause of death of FRDA patients. This work provides the grounds for further evaluation of MB action in mammals.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; Drug Evaluation, Preclinical; Frataxin; Friedreich Ataxia; Gene Knockdown Techniques; Humans; Iron-Binding Proteins; Male; Methylene Blue; RNA Interference; Ubiquinone

It is estimated that one-third of infertility cases are due to male factors. Hyper-cholesterolemia is a social problem in many developed countries and contributed with a heterogeneous group of disorders characterized by an excess of cholesterol and its derivatives in the blood stream.. The objective of the present study was to investigate the protective effects of coenzyme Q10 and L-Carnitine supplementation on semen parameters, sperm function and reproductive hormone profiles in male Wistar rats with high LDL and Oxidized LDL (OxLDL) blood levels.. Animals were fed with cholesterol and oxidized cholesterol-rich diets for 14 weeks to elevate the LDL and OxLDL blood level, respectively. Pretreatment with coenzyme Q10 (10 mg/kg/day, oral) and L-Carnitine (350 mg/kg/day, oral) were conducted for 5 consecutive weeks. Sex hormones levels, malondialdehyde and total antioxidant concentrations, as well as testis, epididymis and seminal vesicle weight were also analyzed.. Following high LDL and OxLDL blood levels, decrease in the sperms count and viability, weights of testis, epididymis and seminal vesicle as well as concentration of testosterone and LH hormone were observed. On the other hand, in contrast to reduction of total antioxidant level, malondialdehyde concentration, both in serum and testis, was increased. However, pretreatment with L-carnitine and coenzyme Q10 increased serum sex hormones level and improved semen parameters significantly.. Overall, pretreatment with coenzyme Q10 and L-Carnitine attenuated the destructive effects of high LDL and oxidized LDL levels on spermatogenesis parameters in male rats.

Topics: Animals; Antioxidants; Carnitine; Cell Survival; Cholesterol, Dietary; Cytoprotection; Disease Models, Animal; Epididymis; Hypercholesterolemia; Infertility, Male; Lipoproteins, LDL; Luteinizing Hormone; Male; Malondialdehyde; Rats, Wistar; Sperm Count; Sperm Motility; Spermatogenesis; Spermatozoa; Testis; Testosterone; Ubiquinone

To test whether a diet supplemented with coenzyme Q10 (CoQ10) ameliorates glutamate excitotoxicity and oxidative stress-mediated retinal ganglion cell (RGC) degeneration by preventing mitochondrial alterations in the retina of glaucomatous DBA/2J mice.. Preglaucomatous DBA/2J and age-matched control DBA/2J-Gpnmb(+) mice were fed with CoQ10 (1%) or a control diet daily for 6 months. The RGC survival and axon preservation were measured by Brn3a and neurofilament immunohistochemistry and by conventional transmission electron microscopy. Glial fibrillary acidic protein (GFAP), superoxide dismutase-2 (SOD2), heme oxygenase-1 (HO1), N-methyl-d-aspartate receptor (NR) 1 and 2A, and Bax and phosphorylated Bad (pBad) protein expression was measured by Western blot analysis. Apoptotic cell death was assessed by TUNEL staining. Mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (Tfam)/oxidative phosphorylation (OXPHOS) complex IV protein expression were measured by real-time PCR and Western blot analysis.. Coenzyme Q10 promoted RGC survival by approximately 29% and preserved the axons in the optic nerve head (ONH), as well as inhibited astroglial activation by decreasing GFAP expression in the retina and ONH of glaucomatous DBA/2J mice. Intriguingly, CoQ10 significantly blocked the upregulation of NR1 and NR2A, as well as of SOD2 and HO1 protein expression in the retina of glaucomatous DBA/2J mice. In addition, CoQ10 significantly prevented apoptotic cell death by decreasing Bax protein expression or by increasing pBad protein expression. More importantly, CoQ10 preserved mtDNA content and Tfam/OXPHOS complex IV protein expression in the retina of glaucomatous DBA/2J mice.. Our findings suggest that CoQ10 may be a promising therapeutic strategy for ameliorating glutamate excitotoxicity and oxidative stress in glaucomatous neurodegeneration.

Topics: Animals; Axons; bcl-Associated Death Protein; Blotting, Western; Disease Models, Animal; Female; Glaucoma; Glial Fibrillary Acidic Protein; Glutamic Acid; Heme Oxygenase-1; In Situ Nick-End Labeling; Membrane Proteins; Mice; Mice, Inbred DBA; Mitochondria; Nerve Tissue Proteins; Oxidative Stress; Real-Time Polymerase Chain Reaction; Receptors, N-Methyl-D-Aspartate; Retinal Degeneration; Retinal Ganglion Cells; Superoxide Dismutase; Ubiquinone; Vitamins

Alzheimer's disease (AD) is the most common fatal neurodegenerative disease affecting the elderly worldwide. There is an urgent need to identify novel biomarkers of early AD. This study aims to search for potential early protein biomarkers in serum from a triple transgenic (PS1M146V/APPSwe/TauP301L) mouse model. Proteomic analysis via two-dimensional fluorescence difference gel electrophoresis was performed on serum samples from wild-type (WT) and triple transgenic mice that were treated with or without coenzyme Q10 (CoQ10) (800 mg/kg body weight/day), a powerful endogenous antioxidant displaying therapeutic benefits against AD pathology and cognitive impairment in multiple AD mouse models, for a period of three months beginning at two months of age. A total of 15 differentially expressed serum proteins were identified between the WT and AD transgenic mice. The administration of CoQ10 was found to alter the changes in the differentially expressed serum proteins by upregulating 10 proteins and down-regulating 10 proteins. Among the proteins modulated by CoQ10, clusterin and α-2-macroglobulin were validated via ELISA assay. These findings revealed significant changes in serum proteins in the AD mouse model at an early pathological stage and demonstrated that administration of CoQ10 could modulate these changes in serum proteins. Our study suggested that these differentially expressed serum proteins could serve as potential protein biomarkers of early AD and that screening for potential candidate AD therapeutic drugs and monitoring of therapeutic effects could be performed via measurement of the changes in these differentially expressed serum proteins.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antioxidants; Blood Proteins; Databases, Protein; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Mutation; Presenilin-1; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; tau Proteins; Ubiquinone

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron degeneration that ultimately results in progressive paralysis and death. Growing evidence indicates that mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in ALS. To further explore the hypothesis that mitochondrial dysfunction and nitroxidative stress contribute to disease pathogenesis at the in vivo level, we assessed whether the mitochondria-targeted antioxidant [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium methane sulfonate (MitoQ) can modify disease progression in the SOD1(G93A) mouse model of ALS. To do this, we administered MitoQ (500 µM) in the drinking water of SOD1(G93A) mice from a time when early symptoms of neurodegeneration become evident at 90 days of age until death. This regime is a clinically plausible scenario and could be more easily translated to patients as this corresponds to initiating treatment of patients after they are first diagnosed with ALS. MitoQ was detected in all tested tissues by liquid chromatography/mass spectrometry after 20 days of administration. MitoQ treatment slowed the decline of mitochondrial function, in both the spinal cord and the quadriceps muscle, as measured by high-resolution respirometry. Importantly, nitroxidative markers and pathological signs in the spinal cord of MitoQ-treated animals were markedly reduced and neuromuscular junctions were recovered associated with a significant increase in hindlimb strength. Finally, MitoQ treatment significantly prolonged the life span of SOD1(G93A) mice. Our results support a role for mitochondrial nitroxidative damage and dysfunction in the pathogenesis of ALS and suggest that mitochondria-targeted antioxidants may be of pharmacological use for ALS treatment.

Topics: Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Disease Models, Animal; Humans; Mice; Mitochondria; Neuroprotective Agents; Organophosphorus Compounds; Oxidative Stress; Ubiquinone

β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD.

Topics: Adenosine Triphosphate; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Caenorhabditis elegans; Disease Models, Animal; Electron Transport Chain Complex Proteins; Gene Expression; Humans; Longevity; Mitochondria; Mitochondrial Membranes; Organophosphorus Compounds; Oxidative Stress; Oxygen Consumption; Protein Carbonylation; Reactive Oxygen Species; Transgenes; Ubiquinone

The aim of this study was to examine the role of coenzyme Q10 (CoQ10) in the prevention of steroid-induced osteonecrosis of the femoral head (ONFH) in rats.. The study included 20 Sprague-Dawley rats injected once with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle to induce osteonecrosis. Animals were divided into two equal groups; Group 1 received no prophylaxis (control group) and the Group 2 received CoQ10. Hematological examinations were performed before steroid injection (0 weeks) and at 4 weeks after steroid injection. Femoral heads were examined histologically to evaluate osteonecrosis.. Changes in blood glutathione (GSH) and malondialdehyde (MDA) concentrations were less significant in the CoQ10 group. The incidence of histologic changes consistent with early osteonecrosis was lower in the CoQ10 group (2 of 10; 20%) than the control group (7 of 10; 70%).. Coenzyme Q10 may be useful as a preventing agent in steroid-induced ONFH. Inhibited oxidative stress is a possible mechanism for this effect.

Topics: Animals; Disease Models, Animal; Femur Head; Glucocorticoids; Glutathione; Malondialdehyde; Methylprednisolone; Methylprednisolone Acetate; Osteonecrosis; Oxidative Stress; Protective Agents; Rats; Rats, Sprague-Dawley; Treatment Outcome; Ubiquinone; Vitamins

HDL and apolipoprotein A1 (apoA1) concentrations inversely correlate with risk of death from ischemic heart disease; however, the role of apoA1 in the myocardial response to ischemia has not been well defined. To test whether apoA1, the primary HDL apolipoprotein, has an acute anti-inflammatory role in ischemic heart disease, we induced myocardial infarction via direct left anterior descending coronary artery ligation in apoA1 null (apoA1(-/-)) and apoA1 heterozygous (apoA1(+/-)) mice. We observed that apoA1(+/-) and apoA1(-/-) mice had a 52% and 125% increase in infarct size as a percentage of area at risk, respectively, compared with wild-type (WT) C57BL/6 mice. Mitochondrial oxidation contributes to tissue damage in ischemia-reperfusion injury. A substantial defect was present at baseline in the electron transport chain of cardiac myocytes from apoA1(-/-) mice localized to the coenzyme Q (CoQ) pool with impaired electron transfer (67% decrease) from complex II to complex III. Administration of coenzyme Q10 (CoQ10) to apoA1 null mice normalized the cardiac mitochondrial CoQ pool and reduced infarct size to that observed in WT mice. CoQ10 administration did not significantly alter infarct size in WT mice. These data identify CoQ pool content leading to impaired mitochondrial function as major contributors to infarct size in the setting of low HDL/apoA1. These data suggest a previously unappreciated mechanism for myocardial stunning, cardiac dysfunction, and muscle pain associated with low HDL and low apoA1 concentrations that can be corrected by CoQ10 supplementation and suggest populations of patients that may benefit particularly from CoQ10 supplementation.

Topics: Animals; Antioxidants; Apolipoprotein A-I; Cardiotonic Agents; Dietary Supplements; Disease Models, Animal; Electron Transport; Electron Transport Complex II; Electron Transport Complex III; Heart; Hypoalphalipoproteinemias; Injections, Intraperitoneal; Intestinal Absorption; Male; Mice; Mice, Knockout; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Tissue Distribution; Ubiquinone

Although the support for the use of antioxidants, such as coenzyme Q(10) (CoQ(10)), to treat Parkinson's disease (PD) comes from the extensive scientific evidence, the results of conducted thus far clinical trials are inconclusive. It is assumed that the efficacy of CoQ(10) is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ(10) (Ubisol-Q(10)) with improved properties, including the brain penetration, and tested its effectiveness in mouse MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) model with the objectives to assess its potential use as an adjuvant therapy for PD. We used a subchronic MPTP model (5-daily MPTP injections), characterized by 50% loss of dopamine neurons over a period of 28 days. Ubisol-Q(10) was delivered in drinking water. Prophylactic application of Ubisol-Q(10), started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q(10) group by day 28). Therapeutic application of Ubisol-Q(10), given after the last MPTP injection, was equally effective. At the time of intervention on day 5 nearly 25% of dopamine neurons were already lost, but the treatment saved the remaining 25% of cells, which otherwise would have died by day 28. This was confirmed by cell counts, analyses of striatal dopamine levels, and improved animals' motor skill on a beam walk test. Similar levels of neuroprotection were obtained with 3 different Ubisol-Q(10) concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ(10)/kg body weight/day, showing clearly that high doses of CoQ(10) were not required to deliver these effects. Furthermore, the Ubisol-Q(10) treatments brought about a robust astrocytic activation in the brain parenchyma, indicating that astroglia played an active role in this neuroprotection. Thus, we have shown for the first time that Ubisol-Q(10) was capable of halting the neurodegeneration already in progress; however, to maintain it a continuous supplementation of Ubisol-Q(10) was required. The pathologic processes initiated by MPTP resumed if supplementation was withdrawn. We suggest that in addition to brain delivery of powerful antioxidants, Ubisol-Q(10) might have also supported subcellular oxidoreductase systems allowing them to maintain a favorable cellular redox status, especially in astroglia, facilitating their role in neuroprotection. Based on this data further clini

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antioxidants; Astrocytes; Chemistry, Pharmaceutical; Disease Models, Animal; Dopaminergic Neurons; Male; Mice, Inbred C57BL; Micelles; Nanoparticles; Neuroprotective Agents; Oxidation-Reduction; Parkinson Disease; Ubiquinone

Coenzyme Q10 is a potent antioxidant in both mitochondria and lipid membranes. It has also been recognized to have an effect on gene expression. This study was designed to investigate whether acute or subchronic treatment with coenzyme Q10 altered the seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated the involvement of nitric oxide in the effects of coenzyme Q10 in pentylenetetrazole-induced seizure models. Acute oral treatment with different doses of coenzyme Q10 did not affect the seizure in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole, and electroshock models in mice. Subchronic oral administration of coenzyme Q10 (100 mg/kg or more) increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole and at the doses of 25 mg/kg or more increased the seizure threshold induced by intravenous infusion of pentylenetetrazole. Subchronic doses of coenzyme Q10 (50 mg/kg or more) also decreased the incidence of tonic seizures in the electroshock-induced seizure model. Moreover, acute treatment with the precursor of nitric oxide synthesis, L-arginine (60 mg/kg), led to a significant potentiation of the antiseizure effects of subchronic administration of coenzyme Q10 (400 mg/kg in intraperitoneal and 6.25 mg/kg in intravenous pentylenetetrazole tests). Acute treatment with l-NAME (5 mg/kg), a nonspecific nitric oxide synthase inhibitor, significantly attenuated the antiseizure effects of subchronic doses of coenzyme Q10 in both seizure models induced by pentylenetetrazole. On the other hand, acute administration of aminoguanidine (100 mg/kg), a specific inducible nitric oxide synthase inhibitor, did not affect the seizures in mice treated with subchronic doses of coenzyme Q10 in both intraperitoneal and intravenous pentylenetetrazole tests. In conclusion, only subchronic and not acute administration of coenzyme Q10 attenuated seizures induced by pentylenetetrazole or electroshock. We also demonstrated, for the first time, the interaction between nitric oxide and coenzyme Q10 in antiseizure activity probably through the induction of constitutive nitric oxide synthase.

Topics: Animals; Arginine; Brain; Disease Models, Animal; Electroshock; Epilepsy, Tonic-Clonic; Guanidines; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pentylenetetrazole; Seizures; Ubiquinone

Parkinson's disease arises from a combination of environmental and genetic risk factors. At present neither the curative nor preventative therapies are available; hence, there is an urgent need to develop reliable animal models to facilitate their development. Water soluble nanomiceller formulation of CoQ10 (Ubisol-Q10) has shown neuroprotection against neurotoxin on human neuronal cells. We have combined the genetic deficiency of DJ-1/PARK7 mice with MPTP exposure and develop a genetic susceptibility model of PD and evaluated the neuroprotective efficacy of (Ubisol-Q10).. Transgenic mice with DJ-1 deficiency (DJ-1/PARK7) were given either water or Ubisol-Q10 prophylactically at a dose of 6 mg/kg/day added directly to a drinking water for one month followed challenged with MPTP injections while keeping the same drinking water regiments. Four weeks after the last injection we evaluated neuroprotective efficacy of Ubisol-Q10 in DJ-1/MPTP model of PD using histochemical and behavioral readouts.. We confirmed genetic susceptibility to MPTP and showed that prophylactic oral treatment with Ubisol-Q10 significantly offset the neurotoxicity and ameliorated motor dysfunction, otherwise correlated with the MPTP injury.. Ubisol-Q10 protects against MPTP-induced neurodegeneration and motor dysfunction in DJ-1 deficient mice. Ubisol-Q10 might be a treatment prospect for people genetically predisposed to PD as well as with sporadic PD.

Topics: Animals; Disease Models, Animal; Genetic Predisposition to Disease; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; MPTP Poisoning; Neurons; Neuroprotective Agents; Oncogene Proteins; Pars Compacta; Peroxiredoxins; Protein Deglycase DJ-1; Tyrosine 3-Monooxygenase; Ubiquinone

The prevalence of metabolic syndrome (MetS) components including obesity, dyslipidemia, insulin resistance (IR), and hepatic steatosis is rapidly increasing in wealthy societies. It is accepted that inflammation/oxidative stress are involved in the initiation/evolution of the MetS features. The present work was designed to evaluate the effects of three major cellular ROS production systems on obesity, glucose tolerance, and hepatic steatosis development and on oxidative stress onset. To do so, 40 young male Sprague-Dawley rats were divided into 5 groups: 1-control group, 2-high fat (HF) group (60% energy from fat), 3-HF+ MitoQ (mitochondrial ROS scavenger), 4-HF+ Apocynin (NADPH oxidase inhibitor), 5-HF+ Allopurinol (xanthine oxidase inhibitor). After 8 weeks of these treatments, surrogate MetS, mitochondrial function, and oxidative stress markers were measured in blood and liver. As expected, rats that were fed the HF diet exhibited increased body weight, glucose intolerance, overt hepatic steatosis, and increased hepatic oxidative stress. The impacts of the studied ROS inhibitors on these aspects of the MetS were markedly different. MitoQ showed the most clinically relevant effects, attenuating body weight gain and glucose intolerance provoked by the HF diet. Both Apocynin and Allopurinol showed limited effects suggesting secondary roles of xanthine oxidase (XO) or NADPH oxidase-dependent ROS production in the onset of oxidative stress-dependent obesity, glucose intolerance, and hepatic steatosis process. Thus, MitoQ revealed the central role of mitochondrial oxidative stress in the development of MetS and suggested that mitochondria-targeted antioxidants may be worth considering as potentially helpful therapies for MetS features.

Topics: Acetophenones; Allopurinol; Animals; Antioxidants; Blotting, Western; Diet, High-Fat; Disease Models, Animal; Male; Metabolic Syndrome; Mitochondria; Obesity; Organophosphorus Compounds; Oxidative Stress; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Ubiquinone

The influence of coenzyme Q10 (CoQ10) on early ischemic deterioration was studied on Wistar rats with experimental myocardial infarction. CoQ10 (30 mg/kg) was injected intravenously 10 min after coronary artery occlusion, and morphometric analysis was performed for 72 h after the onset of ischemia. CoQ10-treated rats had restricted total myocardial damage (by 52%), including areas of necrosis (by 84%) and areas of cellular inflammatory infiltration (by 38%) as compared to saline-treated rats (p < 0.001).

Topics: Animals; Disease Models, Animal; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Ubiquinone; Vitamins

Multiple sclerosis (MS) is known as a progressive central nervous system inflammatory disease. Certain factors, such as interleukins, inflammatory cells, and oxidative stress are supposed to involve in MS etiology. Because of the important role of oxidative stress, antioxidant therapy for MS has received more attention. Although coenzyme Q10 (CoQ10) acts as an antioxidant, there is a lack of enough research on its effects on MS. Therefore, the present research was designed.. C57BL/6 female adult mice (n = 30) were used in this study. The animals were randomly divided into trial and control groups. To induce MS, routine procedure for experimental autoimmune encephalomyelitis (EAE) was used, and scoring was performed based on clinical signs. By detecting score one, CoQ10 administration was started (10 mg/kg/three weeks). By using ELISA and real-time PCR, the brain levels of TNF-, IL-10, IL-4, and IL-12 were studied. Statistical tests were used to analyze the data and the P value less than 0.05 was considered to be significant.. Clinical symptoms in EAE animals were significantly decreased (P<0.05) as compared to control ones. In addition, the level of the TNF- was significantly decreased following CoQ10 administration versus IL-10. The ratio of TH1/TH2 interleukins in treated animals was significantly less than that in non-treated animals (P<0.01).. Our findings showed that CoQ10 is capable of suppressing the inflammatory pathway of MS.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Brain; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression; Interleukin-10; Interleukin-12; Interleukin-4; Mice; Mice, Inbred C57BL; Multiple Sclerosis; RNA, Messenger; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha; Ubiquinone

Accelerating wound healing after tooth extraction is beneficial in dental treatment. Application of antioxidants, such as reduced coenzyme Q10 (rCoQ10), may promote wound healing after tooth extraction. In this study, we examined the effects of topical application of rCoQ10 on wound healing after tooth extraction in rats. After maxillary first molars were extracted, male Fischer 344 rats (8 weeks old) (n = 27) received topical application of ointment containing 5% rCoQ10 (experimental group) or control ointment (control group) to the sockets for 3 or 8 days (n = 6-7/group). At 3 days after extraction, the experimental group showed higher collagen density and lower numbers of polymorphonuclear leukocytes in the upper part of socket, as compared to the control group (p < 0.05). Gene expression of interleukin-1β, tumor necrosis factor-α and nuclear factor-κB were also lower in the experimental group than in the control group (p < 0.05). At 8 days after tooth extraction, there were no significant differences in collagen density, number of polymorphonuclear leukocytes and bone fill between the groups. Our results suggest that topical application of rCoQ10 promotes wound healing in the soft tissue of the alveolar socket, but that rCoQ10 has a limited effect on bone remodeling in rats.

Topics: Animals; Antioxidants; Bone and Bones; Bone Remodeling; Collagen; Disease Models, Animal; Imaging, Three-Dimensional; Interleukin-1beta; Male; Neutrophils; NF-kappa B; Ointments; Pilot Projects; Rats; Rats, Inbred F344; Tooth Extraction; Tumor Necrosis Factor-alpha; Ubiquinone; Wound Healing

This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.

Topics: Accessory Atrioventricular Bundle; Acoustic Stimulation; Aldehydes; Analysis of Variance; Animals; Antioxidants; Auditory Pathways; Brain Injuries; Cochlea; Disease Models, Animal; Ethidium; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory; Hearing Loss, Noise-Induced; Male; Oxidative Stress; Rats; Rats, Wistar; Silver Staining; Ubiquinone; Visual Cortex

Friedreich's ataxia (FRDA), the most common inherited ataxia, is a neurodegenerative disease caused by a reduction in the levels of the mitochondrial protein frataxin, the function of which remains a controversial matter. Several therapeutic approaches are being developed to increase frataxin expression and reduce the intramitochondrial iron aggregates and oxidative damage found in this disease. In this study, we tested separately the response of a Drosophila RNAi model of FRDA (Llorens et al., 2007) to treatment with the iron chelator deferiprone (DFP) and the antioxidant idebenone (IDE), which are both in clinical trials. The FRDA flies have a shortened life span and impaired motor coordination, and these phenotypes are more pronounced in oxidative stress conditions. In addition, under hyperoxia, the activity of the mitochondrial enzyme aconitase is strongly reduced in the FRDA flies. This study reports that DFP and IDE improve the life span and motor ability of frataxin-depleted flies. We show that DFP eliminates the excess of labile iron in the mitochondria and thus prevents the toxicity induced by iron accumulation. IDE treatment rescues aconitase activity in hyperoxic conditions. These results validate the use of our Drosophila model of FRDA to screen for therapeutic molecules to treat this disease.

Topics: Aconitate Hydratase; Animals; Antioxidants; Deferiprone; Disease Models, Animal; Drosophila; Frataxin; Friedreich Ataxia; Hyperoxia; Iron; Iron-Binding Proteins; Mitochondria; Mutation; Oxidative Stress; Phenotype; Pyridones; Ubiquinone

Myocardial ischemia (MI) remains one of the leading causes of death worldwide. Angiogenic therapy with the vascular endothelial growth factor (VEGF) is a promising strategy to overcome hypoxia and its consequences. However, from the clinical data it is clear that fulfillment of the potential of VEGF warrants a better delivery strategy. On the other hand, the compelling evidences of the role of oxidative stress in diseases like MI encourage the use of antioxidant agents. Coenzyme Q10 (CoQ10) due to its role in the electron transport chain in the mitochondria seems to be a good candidate to manage MI but is associated with poor biopharmaceutical properties seeking better delivery approaches. The female Sprague Dawley rats were induced MI and were followed up with VEGF microparticles intramyocardially and CoQ10 nanoparticles orally or their combination with appropriate controls. Cardiac function was assessed by measuring ejection fraction before and after three months of therapy. Results demonstrate significant improvement in the ejection fraction after three months with both treatment forms individually; however the combination therapy failed to offer any synergism. In conclusion, VEGF microparticles and CoQ10 nanoparticles can be considered as promising strategies for managing MI.

Topics: Animals; Cell Proliferation; Coronary Vessels; Disease Models, Animal; Female; Human Umbilical Vein Endothelial Cells; Humans; Lactic Acid; Myocardial Ischemia; Myocardium; Nanoparticles; Neovascularization, Physiologic; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Stroke Volume; Ubiquinone; Vascular Endothelial Growth Factor A

The early onset of type 2 diabetes mellitus (DM), driven by increasing obesity, is associated with peripheral neuropathy. Here, we characterize diabetic neuropathic pain in New Zealand obese diabetic mice (NZO/HILtJ) as a polygenic model of obesity with type 2 diabetes and investigate the role of coenzyme Q10 (CoQ10) in the prevention and treatment of diabetic neuropathic pain. Since the overexpression of mitogen-activated protein kinase (MAPK), nuclear factor-κB proteins (NF-Kb), toll-like receptor 4 (TLR4) and downstream cytokines (such as CCL2, CXCL10) are considered important factors contributing to the development of neuropathic pain, the expression of these factors and the inhibitory effects of CoQ10 were evaluated. NZO/HILtJ mice spontaneously developed type 2 DM and increased body mass with diabetic neuropathic pain. CoQ10 treatment decreased pain hypersensitivity and long-term supplementation prevented the development of diabetic neuropathic pain but did not attenuate diabetes. Spinal cord, blood serum, liver tissue, and dorsal root ganglia (DRG) from diabetic mice demonstrated increased lipid peroxidation, which was decreased by CoQ10 treatment. The percentage of positive neurons of p65 (the activated marker of NF-KB) and MAPK in DRG were significantly higher in DM mice compared to controls. However, CoQ10 treatment significantly decreased p65 and MAPK positive neurons in the DRG of DM mice. RT-PCR demonstrated that elevated levels of mRNA of CCL2, CXCL10 or TLR4 in the spinal cord of DM mice decreased significantly when DM mice were treated with CoQ10.. This model may be useful in understanding the mechanisms of neuropathic pain in type 2 DM induced neuropathic pain and may facilitate preclinical testing of therapies. CoQ10 may decrease oxidative stress in the central and peripheral nervous system by acting as an anti-oxidant and free-radical scavenger. These results suggest that CoQ10 might be a reasonable preventative strategy for long-term use and using CoQ10 treatment may be a safe and effective long-term approach in the treatment of diabetic neuropathy.

Topics: Age Factors; Animals; Blood Glucose; Body Weight; Chemokine CCL2; Chemokine CXCL10; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Models, Animal; Female; Gene Expression Regulation; Hyperalgesia; Lipid Peroxidation; Male; Mice; Pain Measurement; Pain Threshold; Recombinant Fusion Proteins; Toll-Like Receptor 4; Ubiquinone; Vitamins

To investigate the effects of coenzyme Q10 pretreatment on the expressions of Bcl-2, Bax and glycogen synthase kinase-3β (GSK-3β) in rats suffering from ischemia/reperfusion injury.. Thirty-six adult male SD rats were randomly assigned into 3 groups: sham-operated group (sham), ischemia/reperfusion group (I/R) and coenzyme Q10 preconditioning group (Q10). Focal cerebral ischemia/reperfusion models were established in experimental rats by blocking middle cerebral artery with suture. Histological changes of hippocampal neurons were observed by HE staining. The expressions of Bcl-2, Bax and GSK-3β were detected by immunohistochemistry and Western blotting.. Immunohistochemistry showed that the percentage of Bcl-2 positive cells increased in the hippocampus, while the percentages of Bax and GSK-3β positive cells decreased in Q10 group compared with I/R group. Western blotting revealed that the expression level of Bcl-2 was higher and the expression levels of Bax and GSK-3β were lower in Q10 group than in I/R group. There were significant differences between the two groups (P<0.05).. Coenzyme Q10 promoted the expression of Bcl-2 and suppressed the expressions of Bax and GSK-3β in the hippocampus of rats exposed to cerebral ischemia/reperfusion.

Topics: Animals; bcl-2-Associated X Protein; Brain Ischemia; CA1 Region, Hippocampal; Disease Models, Animal; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Proto-Oncogene Proteins c-bcl-2; Rats; Reperfusion Injury; Ubiquinone

Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ. The UQ biosynthetic precursor DMQ9 accumulates in these cells and can sustain mitochondrial respiration, albeit inefficiently. We demonstrated that efficient rescue of the respiratory deficiency in UQ-deficient cells by UQ analogues is side chain length dependent, and that classical UQ analogues with alkyl side chains such as idebenone and decylUQ are inefficient in comparison with analogues with isoprenoid side chains. Furthermore, Vitamin K2, which has an isoprenoid side chain, and has been proposed to be a mitochondrial electron carrier, had no efficacy on UQ-deficient mouse cells. In our model with liver-specific loss of Mclk1, a large depletion of UQ in hepatocytes caused only a mild impairment of respiratory chain function and no gross abnormalities. In conjunction with previous findings, this surprisingly small effect of UQ depletion indicates a nonlinear dependence of mitochondrial respiratory capacity on UQ content. With this model, we also showed that diet-derived UQ10 is able to functionally rescue the electron transport deficit due to severe endogenous UQ deficiency in the liver, an organ capable of absorbing exogenous UQ.

Topics: Alleles; Animals; Ataxia; Cell Respiration; Cell Survival; Disease Models, Animal; Electron Transport; Liver; Membrane Proteins; Mice; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Mixed Function Oxygenases; Muscle Weakness; Oxygen Consumption; Ubiquinone; Vitamin K 2

Oxidative stress and mitochondrial dysfunction appear to contribute to neurodegenerative processes during multiple sclerosis (MS). Thus, antioxidants may represent a therapeutic option for MS. The antioxidant idebenone was proven to be beneficial in Friedreich's ataxia and Leber's hereditary optic neuropathy, two disorders caused by mitochondrial alterations. Here we showed that idebenone protected neuronal HT22 cells from glutamate-induced death in vitro. However, in experimental autoimmune encephalomyelitis, idebenone failed to affect disease incidence or onset when applied preventively, or to reduce disease severity when applied therapeutically. Histopathological examination of CNS from idebenone treated mice showed no improvement in inflammation, demyelination, or axonal damage. Thus, we hypothesize that idebenone treatment will likely not benefit patients with MS.

Topics: Animals; Antioxidants; Chronic Disease; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Hippocampus; Inflammation; Mice; Mice, Inbred C57BL; Neurons; Severity of Illness Index; Ubiquinone

To investigate the effect of CoenzymeQ10 (CoQ10) on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA).. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration of CoQ10 was initiated on day 4 after MIA injection. Pain severity was assessed by measuring secondary tactile allodynia using the von Frey assessment test. The degree of cartilage degradation was determined by measuring cartilage thickness and the amount of proteoglycan. The mankin scoring system was also used. Expressions of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), IL-6, IL-15, inducible nitric oxide synthase (iNOS), nitrotyrosine and receptor for advanced glycation end products (RAGE) were analyzed using immunohistochemistry.. Treatment with CoQ10 demonstrated an antinociceptive effect in the OA animal model. The reduction in secondary tactile allodynia was shown by an increased pain withdrawal latency and pain withdrawal threshold. CoQ10 also attenuated cartilage degeneration in the osteoarthritic joints. MMP-13, IL-1β, IL-6, IL-15, iNOS, nitrotyrosine and RAGE expressions were upregulated in OA joints and significantly reduced with CoQ10 treatment.. CoQ10 exerts a therapeutic effect on OA via pain suppression and cartilage degeneration by inhibiting inflammatory mediators, which play a vital role in OA pathogenesis.

Topics: Analgesics; Animals; Cartilage; Cytokines; Disease Models, Animal; Gene Expression Regulation; Inflammation; Iodoacetic Acid; Male; Matrix Metalloproteinase 13; Nitric Oxide; Nitric Oxide Synthase Type II; Osteoarthritis; Pain; Rats; Rats, Wistar; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Ubiquinone

MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.. Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.. Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.. Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

Topics: Animals; Antioxidants; Carrier Proteins; Cells, Cultured; Colitis; Disease Models, Animal; Drug Delivery Systems; Female; Humans; Inflammasomes; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Organophosphorus Compounds; Reactive Oxygen Species; Ubiquinone

Several recent studies suggest a close link between mitochondrial dysfunction and depression. Coenzyme Q10 (CoQ10) is a mobile electron carrier in the mitochondrial respiratory chain (MRC) with antioxidant and potential neuroprotective activities. This study investigated the effect of chronic administration of CoQ10 (50, 100, and 200 mg/kg/day, intraperitoneally, for 4 weeks) on anhedonia and on the activities of MRC complexes and creatine kinase in the frontal cortex and hippocampus of Wistar rats subjected to chronic restraint stress (CRS, 6 h × 28 days). Exposure to CRS-induced anhedonic-like behavior (decreased sucrose preference), reduced body weight gain and food intake, increased adrenal gland weight, and altered the activity of the MRC complexes in the brain areas tested. CoQ10 dose-dependently antagonized CRS-induced depressive behavior by increasing sucrose preference (reversal of anhedonia), body weight, and food intake and reducing adrenal gland weight. CoQ10 also enhanced the activities of MRC complexes (I-IV) and creatine kinase in the frontal cortex and hippocampus. Thus, the reversal of CRS-induced anhedonia may be partially mediated by amelioration of brain mitochondrial function. The findings also support the hypothesis that brain energy impairment is involved in the pathophysiology of depression and enhancing mitochondrial function could provide an opportunity for development of a potentially more efficient drug therapy for depression.

Topics: Anhedonia; Animals; Antioxidants; Brain; Creatine Kinase; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Electron Transport; Male; Mitochondria; Rats; Rats, Wistar; Restraint, Physical; Stress, Psychological; Sucrose; Ubiquinone

Oxidative stress and mitochondrial impairment are the main pathogenic mechanisms of Amyotrophic Lateral Sclerosis (ALS), a severe neurodegenerative disease still lacking of effective therapy. Recently, the coenzyme-Q (CoQ) complex, a key component of mitochondrial function and redox-state modulator, has raised interest for ALS treatment. However, while the oxidized form ubiquinone10 was ineffective in ALS patients and modestly effective in mouse models of ALS, no evidence was reported on the effect of the reduced form ubiquinol10, which has better bioavailability and antioxidant properties. In this study we compared the effects of ubiquinone10 and a new stabilized formulation of ubiquinol10 on the disease course of SOD1(G93A) transgenic mice, an experimental model of fALS. Chronic treatments (800 mg/kg/day orally) started from the onset of disease until death, to mimic the clinical trials that only include patients with definite ALS symptoms. Although the plasma levels of CoQ10 were significantly increased by both treatments (from <0.20 to 3.0-3.4 µg/mL), no effect was found on the disease progression and survival of SOD1(G93A) mice. The levels of CoQ10 in the brain and spinal cord of ubiquinone10- or ubiquinol10-treated mice were only slightly higher (≤10%) than the endogenous levels in vehicle-treated mice, indicating poor CNS availability after oral dosing and possibly explaining the lack of pharmacological effects. To further examine this issue, we measured the oxidized and reduced forms of CoQ9/10 in the plasma, brain and spinal cord of symptomatic SOD1(G93A) mice, in comparison with age-matched SOD1(WT). Levels of ubiquinol9/10, but not ubiquinone9/10, were significantly higher in the CNS, but not in plasma, of SOD1(G93A) mice, suggesting that CoQ redox system might participate in the mechanisms trying to counteract the pathology progression. Therefore, the very low increases of CoQ10 induced by oral treatments in CNS might be not sufficient to provide significant neuroprotection in SOD1(G93A) mice.

Topics: Amyotrophic Lateral Sclerosis; Animals; Brain; Central Nervous System; Disease Models, Animal; Disease Progression; Humans; Mice; Mice, Transgenic; Spinal Cord; Superoxide Dismutase; Ubiquinone

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

Topics: Adolescent; Adrenal Cortex Hormones; Amino Acid Sequence; Animals; Cells, Cultured; Child; Consanguinity; Conserved Sequence; Disease Models, Animal; DNA Mutational Analysis; Drosophila Proteins; Drug Resistance; Exome; Fibroblasts; Gene Knockdown Techniques; Humans; Mitochondria; Molecular Sequence Data; Mutation; Nephrotic Syndrome; Podocytes; Protein Kinases; Rats; Sequence Alignment; Sequence Homology, Amino Acid; Ubiquinone; Young Adult; Zebrafish; Zebrafish Proteins

Cisplatin or cis-diamminedichloroplatinum (II) (CDDP) is a cytotoxic chemotherapeutic agent with dose-dependent peripheral neuropathy as a foremost side effect characterised by ataxia, pain, and sensory impairment. Cumulative drug therapy of CDDP is known to produce severe oxidative damage. It mainly targets and accumulates in dorsal root ganglia that in turn cause damage resulting in secondary nerve fibre axonopathy. In the present study, we investigated the neuroprotective effect of the combination of monosodium glutamate (MSG) with three individual antioxidants, that is, resveratrol, alpha-lipoic acid (ALA), and coenzyme Q10 (CoQ10), in cisplatin (2 mg/kg i.p. twice weekly) induced peripheral neuropathy in rats. After 8 weeks of treatment the degree of neuroprotection was determined by measuring behavioral and electrophysiological properties and sciatic nerve lipid peroxidation, as well as glutathione and catalase levels. The results suggested that pretreatment with the combination of MSG (500 mg/kg/day po) with resveratrol (10 mg/kg/day i.p.) or ALA (20 mg/kg/day i.p.) or CoQ10 (10 mg/kg weekly thrice i.p.) exhibited neuroprotective effect. The maximum neuroprotection of MSG was observed in the combination with resveratrol.

Topics: Animals; Behavior, Animal; Catalase; Disease Models, Animal; Drug Therapy, Combination; Glutathione; Lipid Peroxidation; Neural Conduction; Neuroprotective Agents; Peripheral Nervous System Diseases; Psychomotor Performance; Rats; Resveratrol; Sciatic Neuropathy; Sodium Glutamate; Stilbenes; Thioctic Acid; Ubiquinone

Chronic cerebral hypoperfusion (CCH) might account for the cognitive deficits associated with vascular cognitive impairment, but the mechanisms of hypoperfusion insulting to the cognition remain obscure. In the present study, Wistar rats underwent permanent occlusion of bilateral common carotid arteries to induce CCH. 2D-DIGE combined with MALDI-TOF MS was applied to determine the proteins that were differentially expressed in synaptosomes of prefrontal cortex and hippocampus. ATPsynβ, NDUFS1, UQCRC1 and Hsp70 were elevated both in synaptosomes of cortex and hippocampus at week 2 after operation, but subsided to baseline at week 4 except ATPsynβ which was still upregulated in synaptosomes of hippocampus at week 4. IDH3A and PDC-E2 were increased, respectively, in synaptosomes of prefrontal cortex and hippocampus at week 2, and showed no difference when compared to control at week 4. Malate dehydrogenase showed no difference in synaptosomes of prefrontal cortex and hippocampus at week 2, but showed an elevation in synaptosomes of prefrontal cortex at week 4. Our results imply that metabolic reserve and anti-oxidative stress might transiently exist in the early stage of CCH, which probably help cognitive save.

Topics: Analysis of Variance; Animals; Brain; Cerebrovascular Disorders; Chronic Disease; Cognition Disorders; Disease Models, Animal; Electron Transport Chain Complex Proteins; Electrophoresis, Gel, Two-Dimensional; HSP70 Heat-Shock Proteins; Malate Dehydrogenase; Male; Mitochondrial Proton-Translocating ATPases; NADH Dehydrogenase; Rats; Rats, Wistar; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Synaptosomes; Ubiquinone

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Both mitochondrial dysfunction and inflammation have been implicated in the pathophysiology of FM. We have investigated the possible relationship between mitochondrial dysfunction, oxidative stress, and inflammation in FM. We studied 30 women diagnosed with FM and 20 healthy women. Blood mononuclear cells (BMCs) from FM patients showed reduced level of coenzyme Q₁₀ (CoQ₁₀) and mtDNA contents and high level of mitochondrial reactive oxygen species (ROS) and serum tumor necrosis factor (TNF)-alpha and transcript levels. A significant negative correlation between CoQ₁₀ and TNF-alpha levels (r=-0.588; p<0.01), and a positive correlation between ROS and TNF-alpha levels (r=0.791; p<0.001) were observed accompanied by a significant correlation of visual analogical scale with serum TNF-alpha and transcript levels (r=0.4507; p<0.05 and r=0.7089; p<0.001, respectively). TNF-alpha release was observed in an in vitro (BMCs) and in vivo (mice) CoQ₁₀ deficiency model. Oral CoQ₁₀ supplementation restored biochemical parameters and induced a significant improvement in clinical symptoms (p<0.001). These results lead to the hypothesis that inflammation could be a mitochondrial dysfunction-dependent event implicated in the pathophysiology of FM in several patients indicating at mitochondria as a possible new therapeutic target.

Topics: Animals; Disease Models, Animal; Female; Fibromyalgia; Humans; Inflammation; Leukocytes, Mononuclear; Male; Mice; Mitochondria; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Ubiquinone

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and the most resistant type to treatment. Novel treatment approaches are strongly required to prevent or even reverse the cellular and molecular mechanisms of epileptogenesis. In this study, we investigated the possible neuroprotective effect of coenzyme Q10 (CoQ10) in an intrahippocampal kainate model of TLE in rat. Kainate injection caused a higher seizure severity during status epilepticus and spontaneous seizure phases, and CoQ10 pretreatment significantly attenuated its severity and incidence rate. Intrahippocampal kainate also led to elevation of malondialdehyde (MDA) and nitrite, and CoQ10 significantly attenuated the increased MDA and nitrite content. In addition, intrahippocampal kainate induced a significant degeneration of neurons in CA1, CA3, and hilar regions of the hippocampus, and CoQ10 significantly attenuated these changes in CA1 and CA3 regions. Timm's staining data showed a robust mossy fiber sprouting (MFS) in dentate gyrus of kainate-lesioned rats and CoQ10 significantly lowered MFS intensity. These data suggest that CoQ10 pretreatment could attenuate spontaneous recurrent seizures and inhibit hippocampal neuronal loss and aberrant MFS in kainate-induced model of TLE in rat, and part of its beneficial effect is due to its potential to mitigate oxidative stress.

Topics: Animals; Cell Death; Disease Models, Animal; Epilepsy, Temporal Lobe; Kainic Acid; Malondialdehyde; Mossy Fibers, Hippocampal; Neuroprotective Agents; Nitrites; Oxidative Stress; Rats; Status Epilepticus; Ubiquinone; Vitamins

The aim of the present investigation was to evaluate the effect of Coenzyme Q10 and its combination with vitamin E in alcohol-induced chronic neuropathic pain. Male Wistar rats were orally treated with alcohol (10 g/kg, 35% v/v, b.i.d.) for 10 weeks. Coenzyme Q10 (25, 50, and 100 mg/kg) and vitamin E (100 mg/kg) were coadministered orally for 1 h after ethanol administration for 10 weeks. Various nerve functions, biochemical, and molecular parameters were assessed. Chronic administration of ethanol for 10 weeks resulted significant development of neuropathic pain. Treatment with Coenzyme Q10 (50 and 100 mg/kg) for 10 weeks showed significant and dose dependently increased in level of nociceptive threshold, endogenous antioxidant, and Na,K-ATPase enzyme. Coenzyme Q10 (50 and 100 mg/kg) significantly restored the levels of motor nerve conduction velocity and sensory nerve conduction velocity. It also showed significant decrease in levels of endogenous calcium, oxidative-nitrosative stress, TNF-α, IL-1β, and IL-4 level. Alteration in protein expression of polymerase gamma (pol γ) was significantly restored the Coenzyme Q10 treatment. The important finding of the study is that, Coenzyme Q10 (100 mg/kg) and α-tocopherol (100 mg/kg) combination-treated rats showed more significant prevention of behavioral, biochemical, and molecular neurotoxic effect of alcohol administration than Coenzyme Q10 or α-tocopherol alone treated group. It is evident from the finding of present investigation that plethora of mechanism including inhibition of oxido-nitrosative stress, release of pro-inflammatory cytokine, modulation of endogenous biomarker, and protection of pol γ protein expression simultaneously orchestrate to exhibits neuroprotective effect of Coenzyme Q10, vitamin E and their combination.

Topics: Administration, Oral; Alcoholic Neuropathy; Animals; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethanol; Interleukin-1beta; Interleukin-4; Male; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Ubiquinone; Vitamin E

Coenzyme Q10 (CoQ) is widely available as a dietary supplement and remains under consideration as a treatment for age-associated neurodegenerative conditions. However, no studies have determined if supplementation, initiated relatively late in life, could have beneficial effects on mild functional impairments associated with normal brain aging. Accordingly, the current study assessed the effect of CoQ intake in older mice for which cognitive and psychomotor impairments were already evident. Separate groups of young (3.5 months) and relatively old mice (17.5 months) were fed a control diet or a diet supplemented with low (0.72 mg/g) or high (2.81 mg/g) concentrations of CoQ for 15 weeks. After 6 weeks, the mice were given tests for spatial learning (Morris water maze), spontaneous locomotor activity, motor coordination, and startle reflex. Age-related impairments in cognitive and psychomotor functions were evident in the 17.5-month-old mice fed the control diet, and the low-CoQ diet failed to affect any aspect of the impaired performance. However, in the Morris water maze test, old mice on the high-CoQ diet swam to the safe platform with greater efficiency than the mice on the control diet. The old mice supplemented with the high-CoQ diet did not show improvement when spatial performance was measured using probe trials and failed to show improvement in other tests of behavioral performance. Protein oxidative damage was decreased in the mitochondria from the heart, liver, and skeletal muscle of the high-CoQ-supplemented mice and, to some extent, in the brain mitochondria. Contrasting with the deleterious effect of long-term CoQ supplementation initiated during young adulthood previously published, this study suggests that CoQ improves spatial learning and attenuates oxidative damage when administered in relatively high doses and delayed until early senescence, after age-related declines have occurred. Thus, in individuals with age-associated symptoms of cognitive decline, high-CoQ intake may be beneficial.

Topics: Aging; Animals; Behavior, Animal; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Learning; Locomotion; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Proteins; Ubiquinone; Vitamins

We investigated the protective effects of coenzyme Q10 on bladder dysfunction in a rat model of atherosclerosis induced chronic bladder ischemia.. A total of 24 male Sprague-Dawley® rats at age 16 weeks were divided into 4 groups of 6 each, including group 1--untreated, sham operated rats, group 2--coenzyme Q10 treated, sham operated rats, group 3--untreated rats with chronic bladder ischemia and group 4--coenzyme Q10 treated rats with chronic bladder ischemia. Groups 3 and 4 received an endothelial injury to the iliac arteries and were fed a 2% cholesterol diet for 8 weeks. Groups 2 and 4 were treated with coenzyme Q10 and the others were treated with vehicle for 4 weeks. Eight weeks postoperatively we performed continuous in vivo cystometry, an in vitro detrusor muscle strip study and a malondialdehyde assay. Histological examination of the bladder walls and iliac arteries was also done.. In vivo cystometry revealed that coenzyme Q10 administration after the induction of chronic bladder ischemia prolonged micturition frequency and the intercontraction interval, and increased bladder capacity compared to those in untreated rats with chronic bladder ischemia. In the detrusor muscle strip study coenzyme Q10 administration after the induction of chronic bladder ischemia increased contractile responses compared to those in untreated rats with chronic bladder ischemia. Rats with chronic bladder ischemia also showed higher malondialdehyde in bladder tissue and serum than the other groups. Chronic bladder ischemia induced submucosal fibrosis of the bladder walls and a degenerative change in the blood vessel tunical media, as shown on histological examination.. Our study suggests that coenzyme Q10 acts as an antioxidant to protect bladder function in this chronic bladder ischemia model.

Topics: Animals; Biopsy, Needle; Chronic Disease; Disease Models, Animal; Immunohistochemistry; Ischemia; Male; Malondialdehyde; Muscle Contraction; Oxidative Stress; Protective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity; Ubiquinone; Urinary Bladder; Urinary Bladder, Overactive; Urodynamics

Multiple evidences suggest that depression is accompanied by an induction of oxidative/nitrosative stress (O&NS) pathways and by a reduced antioxidant status. Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial electron transport pathway and has a powerful antioxidant capacity.. This study investigated the effect of chronic treatment with CoQ10 (25, 50, 100 and 150 mg/kg/day, i.p. for 3 weeks) on depressive-like behavior and hippocampal, O&NS, and DNA damage, induced by chronic restraint stress (CRS), an experimental model of depression, in rats.. CoQ10 showed a significant antidepressant effect, as evidenced by amelioration of CRS-induced behavioral aberrations in forced swimming and open field tests, elevated corticosterone level and body weight loss. Moreover, CoQ10 dose-dependently restored the hippocampal catalase, glutathione peroxidase and reduced glutathione and decreased the hippocampal malondialdehyde, nitric oxide and 8-hydroxy-2'-deoxyguanosine levels, which indicated a potential protective effect of CoQ10 against hippocampal O&NS lipid peroxidation and DNA damage.. CoQ10 possesses antidepressant activity and can protect against CRS-induced hippocampal DNA damage which could be mediated in part by maintaining mitochondrial function and its well documented antioxidant properties. Therefore, CoQ10 may have a potential therapeutic value for the management of depressive disorders. However, further research, is still required to characterize the mechanism of the antidepressant effect of CoQ10 and extend these results before the safe application in humans.

Topics: Animals; Antidepressive Agents; Antioxidants; Behavior, Animal; Corticosterone; Depression; Disease Models, Animal; DNA Damage; Hippocampus; Male; Oxidative Stress; Rats; Rats, Wistar; Reactive Nitrogen Species; Restraint, Physical; Stress, Physiological; Ubiquinone

Oxidative stress is a key factor implicated in the development of diabetic neuropathy. This study evaluates the prophylactic and antinociceptive effects of the antioxidant coenzyme Q10 (CoQ10) on diabetes-induced neuropathic pain in a diabetic mouse model.. Total 56 mice with type 1 diabetes induced by streptozotocin were used, 20 normal mice were used as control. Mechanical and thermal nociceptive behavioral assays were applied to evaluate diabetic neuropathic pain. Tissue lipid peroxidation, immunohistochemistry, reverse transcription, and polymerase chain reaction were used to evaluate the molecular mechanisms of CoQ10. Data are presented as mean ± SEM.. CoQ10 administration was associated with reduced loss of body weight compared with nontreated diabetic mice, without affecting blood glucose levels. Low dose and long-term administration of CoQ10 prevented the development of neuropathic pain. Treatment with CoQ10 produced a significant dose-dependent inhibition of mechanical allodynia and thermal hyperalgesia in diabetic mice. Dorsal root ganglia, sciatic nerve, and spinal cord tissues from diabetic mice demonstrated increased lipid peroxidation that was reduced by CoQ10 treatment. CoQ10 administration was also noted to reduce the proinflammatory factors in the peripheral and central nervous system.. The results of this study support the hypothesis that hyperglycemia induced neuronal oxidative damage and reactive inflammation may be pathogenic in diabetic neuropathic pain. CoQ10 may be protective by inhibiting oxidative stress and reducing inflammation by down-regulating proinflammatory factors. These results suggest that CoQ10 administration may represent a low-risk, high-reward strategy for preventing or treating diabetic neuropathy.

Topics: Analgesics; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Reverse Transcriptase Polymerase Chain Reaction; Ubiquinone; Vitamins; Weight Loss

Elevated (4 to 7-fold) levels of urinary dolichol and coenzyme Q and substantially longer chain lengths for urinary dolichols have been reported in Smith-Lemli-Opitz Syndrome (SLOS) patients, compared to normal subjects. We investigated the possibility of similar alterations in hepatic, nonsterol isoprenoids in a well-established rat model of SLOS. In this model, the ratio of 7-dehydrocholesterol (7DHC) to cholesterol (Chol) in serum approached 15:1; however, total sterol mass in serum decreased by >80 %. Livers from treated rats had 7DHC/Chol ratios of ~32:1, but the steady-state levels of total sterols were >40 % those of livers from age-matched (3-month-old) control animals. No significant differences in the levels of LDL receptor or HMG-CoA reductase were observed. The levels of dolichol and coenzyme Q were elevated only modestly (by 64 and 31 %, respectively; p < 0.05, N = 6) in the livers of the SLOS rat model compared to controls; moreover, the chain lengths of these isoprenoids were not different in the two groups. We conclude that hepatic isoprenoid synthesis is marginally elevated in this animal model of SLOS, but without preferential shunting to the nonsterol branches (dolichol and coenzyme Q) of the pathway and without alteration of normal dolichol chain lengths.

Topics: Animals; Anticholesteremic Agents; Cholesterol; Dehydrocholesterols; Disease Models, Animal; Dolichols; Humans; Liver; Oxidoreductases Acting on CH-CH Group Donors; Rats; Rats, Sprague-Dawley; Smith-Lemli-Opitz Syndrome; Terpenes; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; Ubiquinone

To examine the hypothesis that resuscitative hypothermia would (1) reduce fluid requirements and reactive oxygen species production during a period of resuscitation and (2) improve survival after hemorrhagic shock (HS) in rats.. Sixteen rats underwent an HS phase (phase I: 0-75 minutes), with pressure-controlled HS at a mean arterial pressure of 30 mm Hg ± 5 mm Hg; a resuscitation phase (phase II: 75-150 minutes), with fluid resuscitation to maintain mean arterial pressure ≥75 mm Hg; and an observation phase (phase III: from 150 minutes to 72 hours). During phase II, eight rats were randomized into a normothermia group (group 1: 38°C) or a hypothermia group (group 2: 34°C). Fluid requirements during phase II and survival at 72 hours were compared between groups. Plasma levels of Vitamin E and %coenzyme Q9 (%CoQ9) were also assessed.. The fluid requirement during resuscitation in phase II was 8.2 ± 1.4 mL/100 g in group 1 versus 2.1 mL/100 g ± 0.7 mL/100 g in group 2 (p < 0.01). Vitamin E level decreased to 10.8 μmol/L ± 1.8 μmol/L during HS in all rats. After resuscitation, it was restored to a baseline level of 15.9 μmol/L ± 3.1 μmol/L in group 2 but remained at 10.2 μmol/L ± 0.8 μmol/L in group 1 (p < 0.05). %CoQ9 did not differ significantly between the groups. At 72 hours, six of eight rats in group 1, and all rats in group 2 survived (NS).. In a rat HS model, hypothermia during resuscitation from HS reduces resuscitation fluid volume required to maintain blood pressure and restores Vitamin E to the baseline level, and appears to have no adverse impact on long survival after HS.

Topics: Animals; Blood Pressure; Disease Models, Animal; Fluid Therapy; Hemodynamics; Hypothermia, Induced; Male; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Respiratory Rate; Resuscitation; Shock, Hemorrhagic; Ubiquinone; Vitamin E

Accelerated severe lupus nephritis (ASLN), with an acute onset of severe clinical manifestations and histopathologic renal lesions, may represent transformation of mild LN to a severe form of glomerulonephritis. Abnormal activation of T and B cells and/or oxidative stress may play a major role in the pathogenesis of ASLN. This study tested the hypothesis that antroquinonol, a purified compound and major effective component of Antrodia camphorata with antiinflammatory and antioxidant activities, might prevent the transformation of mild LN into higher-grade (severe) nephritis in a murine lupus model.. Experimental ASLN was induced in (NZB×NZW)F1 mice by twice weekly intraperitoneal injections of Salmonella-type lipopolysaccharide (LPS). Starting 2 days after the first dose of LPS, mice were treated daily with antroquinonol, administered by gavage, for different durations up to 5 weeks.. Antroquinonol administration significantly ameliorated the proteinuria, hematuria, impairment of renal function, and development of severe renal lesions, especially cellular crescent formation, neutrophil infiltration, fibrinoid necrosis, and T cell proliferation in the glomerulus, as well as periglomerular interstitial inflammation. Mechanistic analyses revealed that antroquinonol 1) inhibited T cell activation/proliferation, but enhanced Treg cell suppression and reduced renal production of interleukin-18 (IL-18); 2) inhibited production of reactive oxygen species and nitric oxide, but increased activation of Nrf2 in the kidney; and 3) suppressed renal inflammation via blocking of NF-κB activation.. Antroquinonol may have therapeutic potential for the early treatment of ASLN via its differential regulation of T cell function and lowering of IL-18 production, but also via the promotion of Nrf2 activation.

Topics: Animals; B-Lymphocytes; Cell Proliferation; Disease Models, Animal; Disease Progression; Drugs, Chinese Herbal; Immunoglobulin G; Interleukin-18; Kidney; Lupus Nephritis; Lymphocyte Activation; Mice; Mice, Inbred NZB; NF-E2-Related Factor 2; Plant Extracts; T-Lymphocytes; T-Lymphocytes, Regulatory; Ubiquinone

Controversies surround the usefulness of Coenzyme Q10 (CoQ10) in Huntington's disease (HD), an autosomal dominant, fatal, neurodegenerative disease with no cure or disease modifying treatment. CoQ10, an endogenous substrate for electron transport and an anti-oxidant, has been shown in some but not all studies to improve symptoms and survival in mouse models of HD. Previous studies have been conducted in fast-progressing models that better mimic the juvenile forms of HD than the much more common middle-age onset form, possibly accounting for mixed results. Establishing the usefulness of CoQ10 to alter HD disease course in a model that better recapitulates the progressive features of the human disorder is important because clinical trials of CoQ10, which is safe and well tolerated, are being planned in patients. The CAG140 knock-in (KI) mouse model of HD in which an expanded (approximately 120) CAG repeat is inserted in the mouse gene provides a model of the mutation in the proper genomic and protein context. These mice display progressive motor, cognitive and emotional anomalies, transcriptional disturbances and late striatal degeneration. Homozygote mutant CAG140 KI mice and wild-type littermates were fed CoQ10 (0.2%, 0.6%) in chow, and behavioral and pathological markers of disease were examined. CoQ10 improved early behavioral deficits and normalized some transcriptional deficits without altering huntingtin aggregates in striatum. The lower dose (0.2%) was more beneficial than 0.6%. Similar to previous studies, this low dose also induced deleterious effects in open field and rotarod in WT mice, however these effects are of unclear clinical significance in view of the excellent safety profile of CoQ10 in humans. These data confirm that CoQ10 may be beneficial in HD but suggest that maximum benefit may be observed when treatment is begun at early stages of the disease and that dosage may be critical.

Topics: Animals; Behavior, Animal; Dietary Supplements; Disease Models, Animal; Female; Humans; Huntington Disease; Male; Mice; Mice, Transgenic; Motor Activity; Ubiquinone

The present study was carried out to elucidate the effects of coenzyme Q(10) (CoQ(10)) against cognitive impairments induced by dichlorvos (DDVP). We have previously shown organophosphate, DDVP-induced impairments in neurobehavioral indices viz. rota rod, passive avoidance, and water maze tests. In addition to this, we have also reported that chronic DDVP exposure leads to decreased mitochondrial electron transfer activities of cytochrome oxidase along with altered mitochondrial complexes I-III activity. Administration of CoQ(10) (4.5 mg/kg, i.p. for 12 weeks prior to DDVP administration daily) to DDVP-treated rats improved cognitive performance in passive avoidance task and Morris water maze test. Furthermore, CoQ(10) treatment also reduced oxidative stress (as evident by reduced malondialdehyde, decreased ROS and increased Mn-SOD activity) in DDVP-treated rats' hippocampus region, along with enhanced activity of complexes I-III and complex IV. Electron microscope studies of rat hippocampus mitochondria revealed that CoQ(10) administration leads to near normal physiology of mitochondria with well-defined cristae compared with DDVP-treated animals where enlarged mitochondria with distorted cristae are observed. CoQ(10) administration also attenuated neuronal damage in hippocampus as evident from histopathological studies. These results demonstrate the beneficial effects of CoQ(10) against organophosphate-induced cognitive impairments and hippocampal neuronal degeneration.

Topics: Animals; Avoidance Learning; Cognition Disorders; Dichlorvos; Disease Models, Animal; Drug Administration Schedule; Hippocampus; Male; Maze Learning; Mitochondria; Nerve Degeneration; Oxidative Stress; Proton Pumps; Rats; Rats, Wistar; Ubiquinone; Vitamins

We have previously found abrogated ischemia-induced coronary collateral growth in Zucker obese fatty (ZOF) rats compared with Zucker lean (ZLN) rats. Because ZOF rats have structural abnormalities in their mitochondria suggesting dysfunction and also show increased production of O(2), we hypothesized that mitochondrial dysfunction caused by oxidative stress impairs coronary collateral growth in ZOF.. Increased levels of reactive oxygen species were observed in aortic endothelium and smooth muscle cells in ZOF rats compared with ZLN rats. Reactive oxygen species levels were decreased by the mitochondria-targeted antioxidants MitoQuinone (MQ) and MitoTempol (MT) as assessed by MitoSox Red and dihydroethidine staining. Lipid peroxides (a marker of oxidized lipids) were increased in ZOF by ≈47% compared with ZLN rats. The elevation in oxidative stress was accompanied by increased antioxidant enzymes, except glutathione peroxidase-1, and by increased uncoupling protein-2 in ZOF versus ZLN rats. In addition, elevated respiration rates were also observed in the obese compared with lean rats. Administration of MQ significantly normalized the metabolic profiles and reduced lipid peroxides in ZOF rats to the same level observed in lean rats. The protective effect of MQ also suppressed the induction of uncoupling protein-2 in the obese rats. Resolution of mitochondrial oxidative stress by MQ or MT restored coronary collateral growth to the same magnitude observed in ZLN rats in response to repetitive ischemia.. We conclude that mitochondrial oxidative stress and dysfunction play a key role in disrupting coronary collateral growth in obesity and the metabolic syndrome, and elimination of the mitochondrial oxidative stress with MQ or MT rescues collateral growth.

Topics: Animals; Antioxidants; Collateral Circulation; Coronary Vessels; Disease Models, Animal; Lipid Peroxidation; Lipid Peroxides; Male; Metabolic Syndrome; Mitochondria, Heart; Mitochondrial Proteins; Obesity; Organophosphorus Compounds; Oxidative Stress; Piperidines; Rats; Rats, Zucker; Reactive Oxygen Species; Ubiquinone

The potential protective effect of coenzyme Q10 against acute liver injury induced by a single dose of acetaminophen (700 mg/kg, p.o.) was investigated in rats. Coenzyme Q10 treatment was given as two i.p. injections, 10 mg/kg each, at 1 and 12 h following acetaminophen administration. Coenzyme Q10 significantly reduced the levels of serum aminotransferases, suppressed lipid peroxidation, prevented the decreases of reduced glutathione and catalase activity, decreased the elevations of tumor necrosis factor-α and nitric oxide as well as attenuating the reductions of selenium and zinc ions in liver tissue resulting from acetaminophen administration. Histopathological liver tissue damage mediated by acetaminophen was ameliorated by coenzyme Q10. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the acetaminophen-induced overexpression of inducible nitric oxide synthase, nuclear factor-κB, caspase-3 and p53 in liver tissue. It was concluded that coenzyme Q10 protects rat liver against acute acetaminophen hepatotoxicity, most probably through its antioxidant, anti-inflammatory and antiapoptotic effects.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Biomarkers; Caspase 3; Catalase; Chemical and Drug Induced Liver Injury; Cytoprotection; Disease Models, Animal; Drug Administration Schedule; Glutathione; Immunohistochemistry; Injections, Intraperitoneal; Lipid Peroxidation; Liver; Male; Malondialdehyde; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Sprague-Dawley; Selenium; Time Factors; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Ubiquinone; Zinc

Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.. Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.. Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 ± 0.1 vs 0.2 ± 0.1 pmol O(2) s(-1) [mg protein](-1)), glomerular hyperfiltration (502 ± 26 vs 385 ± 3 μl/min), increased proteinuria (21 ± 2 vs 14 ± 1, μg/24 h), mitochondrial fragmentation (fragmentation score 2.4 ± 0.3 vs 0.7 ± 0.1) and size (1.6 ± 0.1 vs 1 ± 0.0 μm) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (-1.1 ± 0.1 pmol O(2) s(-1) [mg protein](-1)). UCP-2 protein levels were similar in untreated control and db/db mice (67 ± 9 vs 67 ± 4 optical density; OD) but were reduced in CoQ10 treated groups (43 ± 2 and 38 ± 7 OD).. db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Glomerular Filtration Rate; Guanosine Diphosphate; Ion Channels; Kidney Glomerulus; Mice; Mitochondria; Mitochondrial Proteins; Oxidative Stress; Oxygen Consumption; Proteinuria; Ubiquinone; Uncoupling Protein 2; Vitamins

An increase in the production of reactive oxygen species is commonly thought to contribute to the development of diabetic cardiomyopathy. This study aimed to assess whether administration of the antioxidant coenzyme Q(10) would protect the diabetic heart against dysfunction and remodelling, using the db/db mouse model of type 2 diabetes. Furthermore, we aimed to compare the efficacy of coenzyme Q(10) to that of the ACE inhibitor ramipril.. Six-week-old non-diabetic db/+ mice and diabetic db/db mice received either normal drinking water or water supplemented with coenzyme Q(10) for 10 weeks. Endpoint cardiac function was assessed by echocardiography and catheterisation. Ventricular tissue was collected for histology, gene expression and protein analysis.. Untreated db/db diabetic mice exhibited hyperglycaemia, accompanied by diastolic dysfunction and adverse structural remodelling, including cardiomyocyte hypertrophy, myocardial fibrosis and increased apoptosis. Systemic lipid peroxidation and myocardial superoxide generation were also elevated in db/db mice. Coenzyme Q(10) and ramipril treatment reduced superoxide generation, ameliorated diastolic dysfunction and reduced cardiomyocyte hypertrophy and fibrosis in db/db mice. Phosphorylation of Akt, although depressed in untreated db/db mice, was restored with coenzyme Q(10) administration. We postulate that preservation of cardioprotective Akt signalling may be a mechanism by which coenzyme Q(10)-treated db/db mice are protected from pathological cardiac hypertrophy.. These data demonstrate that coenzyme Q(10) attenuates oxidative stress and left ventricular diastolic dysfunction and remodelling in the diabetic heart. Addition of coenzyme Q(10) to the current therapy used in diabetic patients with diastolic dysfunction warrants further investigation.

Topics: Animals; Antihypertensive Agents; Apoptosis; Cardiomegaly; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Endomyocardial Fibrosis; Female; Hyperglycemia; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Oxidative Stress; Proto-Oncogene Proteins c-akt; Ramipril; Superoxides; Ubiquinone; Ultrasonography; Ventricular Remodeling; Vitamins

Digitonin solubilizes mitochondrial membrane, breaks the integrity of the respiratory chain and releases two mobile redox-active components: coenzyme Q (CoQ) and cytochrome c (cyt c). In the present study we report the inhibition of glycerol-3-phosphate- and succinate-dependent oxygen consumption rates by digitonin treatment. Our results show that the inhibition of oxygen consumption rates is recovered by the addition of exogenous synthetic analog of CoQ idebenone (hydroxydecyl-ubiquinone; IDB) and cyt c. Glycerol-3-phosphate oxidation rate is recovered to 148 % of control values, whereas succinate-dependent oxidation rate only to 68 %. We find a similar effect on the activities of glycerol-3-phosphate and succinate cytochrome c oxidoreductase. Our results also indicate that succinate-dependent oxidation is less sensitive to digitonin treatment and less activated by IDB in comparison with glycerol-3-phosphate-dependent oxidation. These findings might indicate the different mechanism of the electron transfer from two flavoprotein-dependent dehydrogenases (glycerol-3-phosphate dehydrogenase and succinate dehydrogenase) localized on the outer and inner face of the inner mitochondrial membrane, respectively.

Topics: Animals; Cytochromes c; Digitonin; Disease Models, Animal; Dose-Response Relationship, Drug; Glycerolphosphate Dehydrogenase; Glycerophosphates; Hyperthyroidism; Kinetics; Male; Mitochondria, Liver; Mitochondrial Membranes; Oxidation-Reduction; Oxygen Consumption; Rats; Rats, Wistar; Recovery of Function; Succinate Cytochrome c Oxidoreductase; Succinic Acid; Ubiquinone

Aminoglycosides, such as gentamycin, are well known ototoxic agents. Toxicity occurs via an activation process involving the formation of an iron-gentamycin complex with free radical production. Antioxidants like Q-ter (a soluble formulation of coenzyme Q(10), CoQ(10)), can limit or prevent cellular ototoxic damage. The present study was designed to investigate the possible protective effects of Q-ter on gentamycin ototoxicity in albino guinea pigs (250-300 g). Animals were divided into five experimental groups: I, a sham control group given an intra-peritoneal (I.P.) injection of 0.5 ml saline (SHAM); II, gentamycin group (GM), treated with an injection of gentamycin (100 mg/ kg); III, gentamycin + Q-ter group (GM+Q-ter), treated with gentamycin (same dose as group II) and an I.P. injection of coenzyme Q(10) terclatrate (Q-ter) at 100 mg/kg body weight; IV, injected with gentamycin (100 mg/kg) plus saline; V, treated with Q-ter alone (100 mg/ kg). All animals were treated for 14 consecutive days. Auditory function was evaluated by recording auditory brainstem responses (ABR) at 15 and 30 days from the beginning of treatment. Morphological changes were analyzed by rhodamine-phalloidine staining. Gentamycin-induced progressive high-frequency hearing loss of 45-55 dB SPL. Q-ter therapy slowed and attenuated the progression of hearing loss, yielding a threshold shift of 20 dB. The significant loss of outer hair cells (OHCs) in the cochlear medio-basal turn in gentamycin-treated animals was not observed in the cochleae of animals protected with Q-ter. This study supports the hypothesis that Q-ter interferes with gentamycin-induced free radical formation, and suggests that it may be useful in protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing loss.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Disease Models, Animal; Gentamicins; Guinea Pigs; Hair Cells, Auditory; Hearing Disorders; Hearing Tests; Ubiquinone

Ubiquinone (Q) is a product in the cholesterol synthesis pathway and is an essential component of the respiratory chain in the mitochondrial membrane. In addition, extra-mitochondrial Q has anti-oxidative properties and this fraction is increased during carcinogenesis. The aim of the present study was to investigate if extra-mitochondrial level of Q is affected by statin treatment in a rat model for liver cancer, and if this change correlates with inhibited carcinogenesis. To do this we isolated sub-cellular fractions of rat livers from a previous experiment where we have shown anti-carcinogenic effects of statins. The levels of Q(8), Q(9) and Q(10) were analysed with liquid chromatography-mass spectrometry. The Q(9)-levels, constituting the major part of Q in rats, were not significantly affected in any of the sub-cellular compartments. The levels of Q(10), constituting a minor part of Q in rats but the major part of Q in humans, were significantly decreased by about 60% in the statin treated rats. The decrease was present in all sub-cellular compartments, but was most pronounced in the cytosol. There was a significant correlation between extra-mitochondrial Q(10) levels and inhibited carcinogenesis. No such correlation was observed with extra-mitochondrial Q(9). The reduced Q(10)-levels might be explained by the reduced availability of isoprene units during statin treatment, shifting the synthesis towards isoforms with shorter side-chains. In line with this hypothesis there were increased levels of Q(8)-levels during statin treatment. The results support our previous suggestion that at least part of the anti-carcinogenic effect of statins in our rat model is mediated by effects on synthesis of Q. We also demonstrate a shift in the Q-synthesis pathway towards isoforms with shorter side-chains during statin treatment. The ratio between the different Q-isoforms might be used as a more sensitive marker of statin-induced inhibition of Q than measuring total Q levels.

Topics: Animals; Anticarcinogenic Agents; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoenzymes; Liver Neoplasms; Male; Mitochondria, Liver; Rats; Rats, Inbred F344; Ubiquinone

The goal of our study is to evaluate the effects of antioxidant vitamins (vitamin C and E), Coenzyme Q10 (CoQ10) and dexamethasone (Dxm) in experimental rat models with pulmonary contusion (PC).. Rats were randomly divided into six groups. Except for the control, all subgroups had a moderate pulmonary contusion. Animals in the group I and group II received intraperitoneal saline, group III received 10mg.kg-1 CoQ10 group IV received 100mg.kg-1 vitamin C, group V received 150 mg.kg-1 vitamin E, and group VI received 10mg.kg-1 Dxm. Blood gas analysis, serum nitric oxide (NO) and malondialdehyde (MDA) levels as well as superoxide dismutase (SOD) activity assays, bronchoalveolar lavage (BAL) fluid and histopathological examination were performed.. Administration of CoQ10 resulted in a significant increase in PaO2 values compared with the group I (p = 0.004). Levels of plasma MDA in group II were significantly higher than those in the group I (p = 0.01). Early administration of vitamin C, CoQ10, and Dxm significantly decreased the levels of MDA (p = 0.01). Lung contusion due to blunt trauma significantly decreased SOD activities in rat lung tissue compared with group I (p = 0.01). SOD levels were significantly elevated in animals treated with CoQ10, Vitamin E, or Dxm compared with group II (p = 0.01).. In our study, CoQ10, vitamin C, vitamin E and Dxm had a protective effect on the biochemical and histopathological outcome of PC after experimental blunt thorax trauma.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Dexamethasone; Disease Models, Animal; Histocytochemistry; Lung Injury; Male; Neutrophils; Rats; Rats, Wistar; Statistics, Nonparametric; Ubiquinone; Vitamin E; Vitamins

Leber's hereditary optic neuropathy (LHON) is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC) dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON. It was therefore of interest to study suitable LHON models in vitro and in vivo to identify anatomical correlates for this protective activity. At nanomolar concentrations, idebenone protected the rodent RGC cell line RGC-5 against complex I dysfunction in vitro. Consistent with the reported dosing and observed effects in LHON patients, we describe that in mice, idebenone penetrated into the eye at concentrations equivalent to those which protected RGC-5 cells from complex I dysfunction in vitro. Consequently, we next investigated the protective effect of idebenone in a mouse model of LHON, whereby mitochondrial complex I dysfunction was caused by exposure to rotenone. In this model, idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, idebenone restored the functional loss of vision in this disease model. These results support the pharmacological activity of idebenone and indicate that idebenone holds potential as an effective treatment for vision loss in LHON patients.

Topics: Administration, Oral; Animals; Antioxidants; Cell Line; Cell Survival; Disease Models, Animal; Drug Administration Schedule; Electron Transport Complex I; Humans; Intravitreal Injections; Male; Mice; Mitochondria; Mutation; Optic Atrophy, Hereditary, Leber; Retinal Ganglion Cells; Rotenone; Ubiquinone; Visual Acuity

Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal peptide that enhances glucose-stimulated insulin secretion. Its natural cleavage product GLP-1(9-36)(amide) possesses distinct properties and does not affect insulin secretion. Here we report that pretreatment of hippocampal slices with GLP-1(9-36)(amide) prevented impaired long-term potentiation (LTP) and enhanced long-term depression induced by exogenous amyloid β peptide Aβ((1-42)). Similarly, hippocampal LTP impairments in amyloid precursor protein/presenilin 1 (APP/PS1) mutant mice that model Alzheimer's disease (AD) were prevented by GLP-1(9-36)(amide). In addition, treatment of APP/PS1 mice with GLP-1(9-36)(amide) at an age at which they display impaired spatial and contextual fear memory resulted in a reversal of their memory defects. At the molecular level, GLP-1(9-36)(amide) reduced elevated levels of mitochondrial-derived reactive oxygen species and restored dysregulated Akt-glycogen synthase kinase-3β signaling in the hippocampus of APP/PS1 mice. Our findings suggest that GLP-1(9-36)(amide) treatment may have therapeutic potential for AD and other diseases associated with cognitive dysfunction.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Association Learning; CA3 Region, Hippocampal; Disease Models, Animal; Drug Evaluation, Preclinical; Excitatory Postsynaptic Potentials; Fear; Female; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Memory Disorders; Mice; Mice, Transgenic; Mitochondria; Neuronal Plasticity; Nootropic Agents; Organophosphorus Compounds; Peptide Fragments; Peptides; Presenilin-1; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Ubiquinone

To evaluate if coenzyme Q10 (CoQ10) can protect retinal ganglion cells (RGCs) from apoptosis and, when instilled as eye drops on the cornea, if it can reach the retina and exert its antiapoptotic activity in this area in a mouse model of kainate (KA)-induced retinal damage.. Rat primary or cultured RGCs were subjected to glutamate (50 μM) or chemical hypoxia (Antimycin A, 200 μM) or serum withdrawal (FBS, 0.5%) in the presence or absence of CoQ10 (10 μM). Cell viability was evaluated by light microscopy and fluorescence-activated cell sorting analyses. Apoptosis was evaluated by caspase 3/7 activity and mitochondrion depolarization tetramethylrhodamine ethyl ester analysis. CoQ10 transfer to the retina following its instillation as eye drops on the cornea was quantified by HPLC. Retinal protection by CoQ10 (10 μM) eye drops instilled on the cornea was then evaluated in a mouse model of KA-induced excitotoxic retinal cell apoptosis by cleaved caspase 3 immunohistofluorescence, caspase 3/7 activity assays, and quantification of inhibition of RGC loss.. CoQ10 significantly increased viable cells by preventing RGC apoptosis. Furthermore, when topically applied as eye drops to the cornea, it reached the retina, thus substantially increasing local CoQ10 concentration and protecting retinal layers from apoptosis.. The ability of CoQ10 eye drops to protect retinal cells from apoptosis in the mouse model of KA-induced retinal damage suggests that topical CoQ10 may be evaluated in designing therapies for treating apoptosis-driven retinopathies.

Topics: Administration, Topical; Animals; Antimycin A; Apoptosis; Caspase 3; Caspase 7; Cell Count; Cell Survival; Cells, Cultured; Chromatography, High Pressure Liquid; Cornea; Disease Models, Animal; Dose-Response Relationship, Drug; Fluorescent Antibody Technique, Indirect; Glutamic Acid; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mitochondria; Ophthalmic Solutions; Rabbits; Rats; Rats, Wistar; Retina; Retinal Diseases; Retinal Ganglion Cells; Time Factors; Ubiquinone; Vitamins

The present study aims to clarify the protective effect of supplementation with some antioxidants, such as idebenone (200 mg/kg, ip), melatonin (10 mg/kg, ip) and arginine (200 mg/kg, ip) and their combination, on liver function (T. protein, albumin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase), energetic parameters (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, inorganic phosphate, total adenylate, adenylate energy charge and potential phosphate). The effect on glycolytic and glycogenolytic enzymes (glucose, glycogen, glycogen phosphorylase, pyruvate kinase and phosphofructokinase against hypoxia) was also studied. The drugs were administered 24 and 1 h prior sodium nitrite intoxication. All biochemical parameters were estimated 1 h after sodium nitrite injection. Injection of sodium nitrite (75 mg/kg, sc) produced a significant disturbance in all biochemical parameters of liver function, energetic parameters and glycolytic and glycogenolytic enzymes. Hepatic damage was confirmed by histopathological examination of the liver as compared to controls. The marked changes in hepatic cells induced by sodium nitrite were completely abolished by pretreatment with the drug combination, suggesting potential protection against sodium nitrite-induced hypoxia. It could be concluded that a combination of both idebenone and melatonin or idebenone and arginine provides potential protection against sodium nitrite-induced hypoxia by improving biochemical parameters and preserving liver histology.

Topics: Animals; Antioxidants; Arginine; Chemical and Drug Induced Liver Injury; Cytoprotection; Dietary Supplements; Disease Models, Animal; Drug Therapy, Combination; Energy Metabolism; Hypoxia; Liver; Male; Melatonin; Oxidative Stress; Rats; Reactive Oxygen Species; Sodium Nitrite; Time Factors; Ubiquinone

Partial bladder outlet obstruction (PBOO) in rabbits causes free radical production through ischemia and reperfusion within the bladder smooth muscle and mucosa. We had previously shown that pretreatment of rabbits with a combination of α-lipoic acid (αLA) and coenzyme Q10 (CoQ) protected the bladder from contractile and metabolic dysfunctions mediated by PBOO. In this study, we examined the ability of pretreatment with αLA and CoQ combination in rabbits to protect the bladder from contractile damage mediated by either hydrogen peroxide (H(2)O(2)) or in vitro ischemia-reperfusion (I/R) which represents two in vitro models of oxidative damage.. Eight adult male New Zealand white rabbits were pretreated with CoQ and αLA orally for four weeks. Eight adult male control rabbits were given vehicle. Eight full-thickness bladder strips were isolated from each of 4 treated and 4 control rabbit bladders, and a dose-response curve to H(2)O(2) (0.1-0.8%) was generated. Similarly, isolated strips of bladder from the remaining 4 control and 4 treated rabbits were subjected to 1 h of ischemia (no oxygen without glucose) followed by 2 h of incubation in oxygenated buffer with glucose. The effects on the contractile responses to field stimulation (FS) at 2, 8, and 32 Hz, carbachol, and potassium chloride (KCl) were determined.. H(2)O(2) reduced the contractile responses to KCl and carbachol to a significantly greater degree than to FS, whereas I/R reduced the contractile responses to FS to a significantly greater degree than to KCl and carbachol. Pretreatment of the rabbits with the combination of CoQ and αLA significantly protected the bladder from the damaging effects of I/R, but had virtually no effect on the damaging effects of H(2)O(2).. Although both H(2)O(2) and I/R are in vitro models of oxidative free radical damage to bladder smooth muscle, they have significantly different methods of action and different sensitivities to antioxidants.

Topics: Animals; Antioxidants; Disease Models, Animal; Drug Therapy, Combination; Follow-Up Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Muscle Contraction; Muscle, Smooth; Oxidative Stress; Rabbits; Reperfusion Injury; Thioctic Acid; Ubiquinone; Urinary Bladder Neck Obstruction; Vitamins

In this study, we investigated the effects of lipoic acid (LA) in the hippocampus oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10mg/kg, i.p., LA group), ubiquinone [20mg/kg, i.p., ubiquinone (UQ) group], pilocarpine (400mg/kg, i.p., P400 group), and the association of LA (10mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.) or UQ (20mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.), 30min before of administration of P400 (LA plus P400 group and UQ plus P400 group, respectively). After the treatments, all groups were observed for 1h. The enzyme activities (δ-aminolevulinic dehydratase (δ-ALA-D), Mg(2+) -ATPase, and Na(+) , K(+) -ATPase) were measured using spectrophotometric methods, and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA and UQ were also evaluated on the same parameters. We reported here for the first time that Na(+) , K(+) -ATPase and δ-ALA-D activities inhibition and Mg(2+) -ATPase stimulation in the pilocarpine model are probably attributed to the oxidative stress caused by seizures in the rat hippocampus. The addition of the antioxidants LA and UQ may reverses the previously mentioned Na(+) , K(+) -ATPase and δ-ALA-D inhibitions and Mg(2+) -ATPase stimulation.. The oxidative stress plays an important signaling role in pilocarpine-induced seizures, and antioxidant drugs might be considered as therapeutical tools in this pathology.

Topics: Animals; Antioxidants; Ca(2+) Mg(2+)-ATPase; Disease Models, Animal; Hippocampus; Male; Oxidative Stress; Pilocarpine; Porphobilinogen Synthase; Rats; Rats, Wistar; Seizures; Sodium-Potassium-Exchanging ATPase; Thioctic Acid; Ubiquinone

Mitochondrial disorders are often associated with primary or secondary CoQ10 decrease. In clinical practice, Coenzyme Q10 (CoQ10) levels are measured to diagnose deficiencies and to direct and monitor supplemental therapy. CoQ10 is reduced by complex I or II and oxidized by complex III in the mitochondrial respiratory chain. Therefore, the ratio between the reduced (ubiquinol) and oxidized (ubiquinone) CoQ10 may provide clinically significant information in patients with mitochondrial electron transport chain (ETC) defects. Here, we exploit mutants of Caenorhabditis elegans (C. elegans) with defined defects of the ETC to demonstrate an altered redox ratio in Coenzyme Q9 (CoQ9), the native quinone in these organisms. The percentage of reduced CoQ9 is decreased in complex I (gas-1) and complex II (mev-1) deficient animals, consistent with the diminished activity of these complexes that normally reduce CoQ9. As anticipated, reduced CoQ9 is increased in the complex III deficient mutant (isp-1), since the oxidase activity of the complex is severely defective. These data provide proof of principle of our hypothesis that an altered redox status of CoQ may be present in respiratory complex deficiencies. The assessment of CoQ10 redox status in patients with mitochondrial disorders may be a simple and useful tool to uncover and monitor specific respiratory complex defects.

Topics: Animals; Antioxidants; Caenorhabditis elegans; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Humans; Mitochondria; Mitochondrial Diseases; Oxidation-Reduction; Ubiquinone

The muscular dystrophies (MDs) are genetic disorders of muscle degeneration due to mutations in genes that encode a wide variety of proteins. Dysferlinopathy are characterized by the absence of dysferlin in skeletal muscle and an autosomal recessive mode of inheritance. Both histological and ultrastructural pathology have been well established in dysferlinopathy patients and dysferlin-deficient animal models. To our knowledge the effect of antioxidant supplementation on this level has not been described previously. This article therefore focuses on the histopathology to reveal the effect of antioxidant supplementation. The study aimed to determine, at cellular level, the histopathological changes in the SJL/J mouse model following a 90 day trial with antioxidant supplementation. Markedly reduced inflammatory insult in the more affected quadriceps muscles of animals treated with high doses of CoQ10 and a combination of resveratrol/CoQ10 were observed. The outcome provides evidence that high doses of antioxidant supplementation resulted in decreased dystrophic markers and enhanced tissue integrity at cellular level.

Topics: Animals; Antioxidants; Disease Models, Animal; Female; Mice; Muscle, Skeletal; Muscular Dystrophies; Resveratrol; Stilbenes; Ubiquinone

The role of oxidative stress within photoreceptors (PRs) in inherited photoreceptor degeneration (IPD) is unclear. We investigated this question using four IPD mouse models (Pde6b(rd1/rd1), Pde6b(atrd1/atrd1), Rho(-/-) and Prph2(rds/rds)) and compared the abundance of reduced glutathione (GSH) and the activity of mitochondrial NADH:ubiquinone oxidoreductase (complex I), which is oxidative stress sensitive, as indirect measures of redox status, in the retinas of wild type and IPD mice. All four IPD mutants had significantly reduced retinal complex I activities (14-29% of wild type) and two showed reduced GSH, at a stage prior to the occurrence of significant cell death, whereas mitochondrial citrate synthase, which is oxidative stress insensitive, was unchanged. We orally administered the mitochondrially targeted anti oxidant MitoQ in order to reduce oxidative stress but without any improvement in retinal complex I activity, GSH or rates of PR degeneration. One possible source of oxidative stress in IPDs is oxygen toxicity in the outer retina due to reduced consumption by PR mitochondria. We therefore asked whether a reduction in the ambient O(2) concentration might improve PR survival in Pde6b(rd1/rd1) retinal explants either directly, by reducing reactive oxygen species formation, or indirectly by a neuroprotective mechanism. Pde6b(rd1/rd1) retinal explants cultured in 6% O(2) showed 31% less PR death than normoxic explants. We conclude that (i) mitochondrial oxidative stress is a significant early feature of IPDs; (ii) the ineffectiveness of MitoQ may indicate its inability to reduce some mediators of oxidative stress, such as hydrogen peroxide; and (iii) elucidation of the mechanisms by which hypoxia protects mutant PRs may identify novel neuroprotective pathways in the retina.

Topics: Animals; Antioxidants; Cell Hypoxia; Cell Survival; Disease Models, Animal; Electron Transport Complex I; Glutathione; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Photoreceptor Cells; Retinal Degeneration; Superoxide Dismutase; Ubiquinone

Oxidative stress, inflammation, and fibrosis are involved in the development and progression of focal segmental glomerulosclerosis (FSGS), a common form of idiopathic nephrotic syndrome that represents a therapeutic challenge because it has a poor response to steroids. Antroquinonol (Antroq), a purified compound, is a major active component of a mushroom, namely Antrodia camphorata, that grows in the camphor tree in Taiwan, and it has inhibitory effects on nitric oxide production and inflammatory reactions. We hypothesized that Antroq might ameliorate FSGS renal lesions by modulating the pathogenic pathways of oxidative stress, inflammation, and glomerular sclerosis in the kidney. We demonstrate that Antroq significantly (1) attenuates proteinuria, renal dysfunction, and glomerulopathy, including epithelial hyperplasia lesions and podocyte injury; (2) reduces oxidative stress, leukocyte infiltration, and expression of fibrosis-related proteins in the kidney; (3) increases renal nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase activity; and (4) inhibits renal nuclear factor-κB (NF-κB) activation and decreases levels of transforming growth factor (TGF)-β1 in serum and kidney tissue in a mouse FSGS model. Our data suggest that Antroq might be a potential therapeutic agent for FSGS, acting by boosting Nrf2 activation and suppressing NF-κB-dependent inflammatory and TGF-β1-mediated fibrosis pathways in the kidney.

Topics: Animals; Antrodia; Disease Models, Animal; Female; Focal Epithelial Hyperplasia; Glomerulosclerosis, Focal Segmental; Humans; Inflammation; Kidney; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Sclerosis; Signal Transduction; Transforming Growth Factor beta1; Ubiquinone

Chronic alcohol-induced liver disease results in inflammation, steatosis, and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone (MitoQ) (5 and 25 mg/kg/day for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α), and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis, and induction of cytochrome P450 2E1 (CYP2E1). MitoQ had a minor effect on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities; however, it did decrease hepatic steatosis in ethanol-consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocked the increase in HIF1α in all ethanol-fed groups, which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis.. These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol-associated mitochondrial reactive oxygen species (ROS) and several downstream effects of ROS/RNS (reactive nitrogen species) production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependent HIF1α stabilization.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Cytochrome P-450 CYP2E1; Disease Models, Animal; Dose-Response Relationship, Drug; Electron Transport; Ethanol; Fatty Liver; Hypoxia-Inducible Factor 1, alpha Subunit; Lipid Metabolism; Liver; Male; Mitochondria, Liver; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Ubiquinone

In recent years, the medicinal mushroom Antrodia cinnamomea, known as "niu-chang chih" has received much attention with regard to its possible health benefits; especially its hepatoprotective effects against various drugs, toxins, and alcohol induced liver diseases. However, the molecular mechanism underlying this protective effect of Antrodia cinnamomea and its active compound antroquinonol was poorly understood. In the present study we evaluated to understand the hepatoprotective efficacy of antroquinonol and ethanolic extracts of mycelia of Antrodia cinnamomea (EMAC) in vitro and in vivo.. The protective mechanism of antroquinonol and EMAC against ethanol-induced oxidative stress was investigated in cultured human hepatoma HepG2 cells and ICR mice model, respectively. HepG2 cells were pretreated with antroquinonol (1-20μM) and oxidative stress was induced by ethanol (100mM). Meanwhile, male ICR mice were pretreated with EMAC for 10 days and hepatotoxicity was generated by the addition of ethanol (5g/kg). Hepatic enzymes, cytokines and chemokines were determined using commercially available assay kits. Western blotting and real-time PCR were subjected to analyze HO-1 and Nr-2 expression. EMSA was performed to monitor Nrf-2 ARE binding activity. Possible changes in hepatic lesion were observed using histopathological analysis.. Antroquinonol pretreatment significantly inhibited ethanol-induced AST, ALT, ROS, NO, MDA production and GSH depletion in HepG2 cells. Western blot and RT-PCR analysis showed that antroquinonol enhanced Nrf-2 activation and its downstream antioxidant gene HO-1 via MAPK pathway. This mechanism was then confirmed in vivo in an acute ethanol intoxicated mouse model: serum ALT and AST production, hepatocellular lipid peroxidation and GSH depletion was prevented by EMAC in a dose-dependent manner. EMAC significantly enhanced HO-1 and Nrf-2 activation via MAPKs consistent with in vitro studies. Ethanol-induced hepatic swelling and hydropic degeneration of hepatocytes was significantly inhibited by EMAC in a dose-dependent manner.. These results provide a scientific basis for the hepatoprotective effects of Antrodia cinnamomea. Data also imply that antroquinonol, a potent bioactive compound may be responsible for the hepatoprotective activity of Antrodia cinnamomea. Moreover, the present study highly supported our traditional knowledge that Antrodia cinnamomea as a potential candidate for the treatment of alcoholic liver diseases.

Topics: Animals; Antioxidants; Antrodia; Biological Products; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Glutathione; Heme Oxygenase-1; Hep G2 Cells; Hepatocytes; Humans; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Mycelium; NF-E2-Related Factor 2; Nitric Oxide; Oxidative Stress; Phytotherapy; Reactive Oxygen Species; Transaminases; Ubiquinone

It is known that oxidative stress and mitochondrial dysfunction both play an important role in animal models of brain ischemia. The present study was undertaken to test whether oral supplementation of coenzyme Q10 (ubiquinone) or creatine citrate could protect against brain ischemia-induced mitochondrial damage in the rats model. Brain ischemia was induced for 50 minutes with three-vessel occlusion (3-VO). Coenzyme Q10 was administered for 30 days before the ischemic event and coenzyme Q10 or creatine citrate for 30 days post-ischemia. Moreover, the concentrations of coenzyme Q10 and α-, γ- tocopherols as well as the formation of thiobarbituric acid reactive substances (TBARS) were measured in brain mitochondria and in plasma. Transient hypoperfusion revealed significant impairment in brain energy metabolism as detected by mitochondrial oxidative phosphorylation as well as decreased concentrations of brain and plasma endogenous antioxidants and increased formation of TBARS in plasma. When compared with the ischemic group, supplementation of coenzyme Q10 was ineffective as a preventive agent. However, the positive effect of therapeutic coenzyme Q10 supplementation was supported by the oxygen consumption values (p < 0.05) and ATP production (p < 0.05) in brain mitochondria, as well as by increased concentration of coenzyme Q9 (p < 0.05) and concentration of α-tocopherol (p < 0.05) in brain mitochondria and by increased concentration of α-tocopherol (p < 0.05) and γ-tocopherol in plasma. This suggests that coenzyme Q10 therapy involves resistance to oxidative stress and improved brain bioenergetics, when supplemented during reperfusion after ischemic brain injury.

Topics: Animals; Cerebral Cortex; Chronic Disease; Citrates; Creatine; Dietary Supplements; Disease Models, Animal; Energy Metabolism; Hypoxia-Ischemia, Brain; Male; Micronutrients; Oxidative Stress; Perfusion; Rats; Rats, Wistar; Ubiquinone

Head trauma is one of the most important clinical issues that not only can be fatal and disabling, requiring long-term treatment and care, but also can cause heavy financial burden. Formation or distribution of free oxygen radicals should be decreased to enable fixing of poor neurological outcomes and to prevent neuronal damage secondary to ischemia after trauma. Coenzyme Q₁₀ (CoQ₁₀), a component of the mitochondrial electron transport chain, is a strong antioxidant that plays a role in membrane stabilization. In this study, the role of CoQ₁₀ in the treatment of head trauma is researched by analyzing the histopathological and biochemical effects of CoQ₁₀ administered after experimental traumatic brain injury in rats. A traumatic brain-injury model was created in all rats. Trauma was inflicted on rats by the free fall of an object of 450 g weight from a height of 70 cm on the frontoparietal midline onto a metal disc fixed between the coronal and the lambdoid sutures after a midline incision was carried out.. In the biochemical tests, tissue malondialdehyde (MDA) levels were significantly higher in the traumatic brain-injury group compared to the sham group (p < 0.05). Administration of CoQ₁₀ after trauma was shown to be protective because it significantly lowered the increased MDA levels (p < 0.05). Comparing the superoxide dismutase (SOD) levels of the four groups, trauma + CoQ₁₀ group had SOD levels ranging between those of sham group and traumatic brain-injury group, and no statistically significant increase was detected. Histopathological results showed a statistically significant difference between the CoQ₁₀ and the other trauma-subjected groups with reference to vascular congestion, neuronal loss, nuclear pyknosis, nuclear hyperchromasia, cytoplasmic eosinophilia, and axonal edema (p < 0.05).. Neuronal degenerative findings and the secondary brain damage and ischemia caused by oxidative stress are decreased by CoQ₁₀ use in rats with traumatic brain injury.

Topics: Animals; Brain Injuries; Brain Ischemia; Chromatography, High Pressure Liquid; Disease Models, Animal; Neurons; Rats; Ubiquinone; Vitamins

Conventional antiepileptic drugs fail to adequately control seizures and predispose to cognitive impairment and oxidative stress with chronic usage in a significant proportion of patients with epilepsy. Coenzyme Q10 (CoQ10), an antioxidant compound, exhibits a wide range of therapeutic effects that are attributed to its potent antioxidant capacity. To evaluate the neuroprotective effects of CoQ10 in rats against the observed oxidative stress during seizures induced by pilocarpine, and to study its interactions with the conventional antiepileptic drug phenytoin, two experiments were performed. Experiment 1 was conducted to test the effect of phenytoin, CoQ10, or both on seizure severity and oxidative markers in the pilocarpine model of epilepsy. Experiment 2 was conducted to test the effect of 2 weeks of chronic treatment with phenytoin, CoQ10, or both on oxidative markers and behavioral tests in rats. Overall, CoQ10 reduced the severity of pilocarpine-induced seizures and the severity of oxidative stress. Moreover, it potentiated the antiepileptic effects afforded by phenytoin treatment, with the potential safety and efficacy in ameliorating oxidative stress and cognitive impairment caused by chronic phenytoin therapy. Our findings strongly suggest that CoQ10 can be considered a safe and effective adjuvant to phenytoin therapy in epilepsy both to ameliorate seizure severity and to protect against seizure-induced oxidative damage by reducing the cognitive impairment and oxidative stress associated with chronic use of phenytoin.

Topics: Analysis of Variance; Animals; Anticonvulsants; Avoidance Learning; Catalase; Cognition Disorders; Disease Models, Animal; Drug Synergism; Glutathione; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Phenytoin; Pilocarpine; Psychomotor Performance; Rats; Rats, Wistar; Reaction Time; Severity of Illness Index; Status Epilepticus; Superoxide Dismutase; Ubiquinone

Considerable evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the progression of Alzheimer's disease (AD). We examined the ability of the novel mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cycloheexadienl-yl) decyl triphenylphosphonium methanesulfonate]) to prevent AD-like pathology in mouse cortical neurons in cell culture and in a triple transgenic mouse model of AD (3xTg-AD). MitoQ attenuated β-amyloid (Aβ)-induced neurotoxicity in cortical neurons and also prevented increased production of reactive species and loss of mitochondrial membrane potential (Δψ(m)) in them. To determine whether the mitochondrial protection conferred by MitoQ was sufficient to prevent the emergence of AD-like neuropathology in vivo, we treated young female 3xTg-AD mice with MitoQ for 5 months and analyzed the effect on the progression of AD-like pathologies. Our results show that MitoQ prevented cognitive decline in these mice as well as oxidative stress, Aβ accumulation, astrogliosis, synaptic loss, and caspase activation in their brains. The work presented herein suggests a central role for mitochondria in neurodegeneration and provides evidence supporting the use of mitochondria-targeted therapeutics in diseases involving oxidative stress and metabolic failure, namely AD.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Animals, Newborn; Antioxidants; Caspases; Cell Death; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Glial Fibrillary Acidic Protein; Gliosis; Glutathione; Humans; Lipid Peroxidation; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Neurons; Organophosphorus Compounds; Oxidative Stress; Peptide Fragments; Retention, Psychology; Rhodamines; Space Perception; Time Factors; Tyrosine; Ubiquinone

Preventive action of new antioxidant SkQ1 has been studied in rats on model of cardiac arrhythmia caused by epinephrine. The SkQ1 substance was given in dosages from 0.02 up to 20 moles/kg per os 2 weeks prior to experiment. Intravenous bolus introduction of epinephrine (10 or 6 mkg/kg in different experimental series) caused an immediate rise of arterial pressure in average by 19% and decrease in heart rate in average by 44%. The degree of changes of these parameters was approximately identical in all groups. Arrhythmia in the form of ventricular extrasystolia arose in the first 5 min. The total number of extrasystoles, and index of arrhythmia intensity have been 2-3 times lower in rats receiding SkQ1 in doses of 0.5, 2 and 20 moles/kg. It was combined with increased survival rate of animals. Smaller dosages of SkQ1 (0.02-0.1 moles/kg) were ineffective. Results have shown that administration of mitochondrial antioxidant SkQ1 raises stability of the myocardium to arrhythmogenic action of epinephrine.

Topics: Animals; Antioxidants; Arrhythmias, Cardiac; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Electron Transport; Epinephrine; Heart Rate; Male; Membrane Potential, Mitochondrial; Myocytes, Cardiac; Rats; Rats, Wistar; Therapies, Investigational; Treatment Outcome; Ubiquinone

In this experimental study, we assessed the preventive effects of coenzyme Q(10) (CoQ(10)) in a rat model of ischemia/reperfusion injury. The results of this study show that CoQ(10) administration before the reperfusion period of testicular torsion provides a significant decrease in testicular lipid peroxidation products and expressions of inducible nitric oxide synthase, endothelial nitric oxide synthase, and germ cell-specific apoptosis.

Topics: Animals; Apoptosis; Disease Models, Animal; Down-Regulation; Lipid Peroxidation; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Reperfusion Injury; Spermatic Cord Torsion; Testis; Ubiquinone

We previously reported that coenzyme Q10 (CoQ10) could reduce intracellular deposition in an aged transgenic mouse model. Here, we further tested the effect of CoQ10 on amyloid plaque in an amyloid precursor protein/presenilin 1 transgenic mouse model of Alzheimer's disease (AD). By using immunohistochemistry and magnetic resonance imaging to determine the burden of amyloid plaque, we found that oral administration of CoQ10 can efficiently reduce the burden of the plaques in this mouse model. These data demonstrate that in addition to reducing intracellular deposition of Abeta, CoQ10 can also reduce plaque pathology. Our study further supports the use of CoQ10 as a therapeutic candidate for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Disease Models, Animal; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Neuroprotective Agents; Plaque, Amyloid; Presenilin-1; Ubiquinone; Vitamins

Microarray expression profiling has become a valuable tool in the evaluation of the genetic consequences of metabolic disease. Although 3'-biased gene expression microarray platforms were the first generation to have widespread availability, newer platforms are gradually emerging that have more up-to-date content and/or higher cost efficiency. Deciphering the relative strengths and weaknesses of these various platforms for metabolic pathway-level analyses can be daunting. We sought to determine the practical strengths and weaknesses of four leading commercially available expression array platforms relative to biologic investigations, as well as assess the feasibility of cross-platform data integration for purposes of biochemical pathway analyses.. Liver RNA from B6.Alb/cre,Pdss2(loxP/loxP) mice having primary coenzyme Q deficiency was extracted either at baseline or following treatment with an antioxidant/antihyperlipidemic agent, probucol. Target RNA samples were prepared and hybridized to Affymetrix 430 2.0, Affymetrix Gene 1.0 ST, Affymetrix Exon 1.0 ST, and Illumina Mouse WG-6 expression arrays. Probes on all platforms were re-mapped to coding sequences in the current version of the mouse genome. Data processing and statistical analysis were performed by R/Bioconductor functions, and pathway analyses were carried out by KEGG Atlas and GSEA.. Expression measurements were generally consistent across platforms. However, intensive probe-level comparison suggested that differences in probe locations were a major source of inter-platform variance. In addition, genes expressed at low or intermediate levels had lower inter-platform reproducibility than highly expressed genes. All platforms showed similar patterns of differential expression between sample groups, with 'steroid biosynthesis' consistently identified as the most down-regulated metabolic pathway by probucol treatment.. This work offers a timely guide for metabolic disease investigators to enable informed end-user decisions regarding choice of expression microarray platform best-suited to specific research project goals. Successful cross-platform integration of biochemical pathway expression data is also demonstrated, especially for well-annotated and highly expressed genes. However, integration of gene-level expression data is limited by individual platform probe design and the expression level of target genes. Cross-platform analyses of biochemical pathway data will require additional data processing and novel computational bioinformatics tools to address unique statistical challenges.

Topics: Animals; Antioxidants; Computational Biology; Disease Models, Animal; Gene Expression Profiling; Mice; Mice, Knockout; Mitochondrial Diseases; Oligonucleotide Array Sequence Analysis; Probucol; Proteins; RNA; Treatment Outcome; Ubiquinone

Dietary coenzyme Q10 reduces spontaneous atherosclerosis in the apoE-deficient mouse model of experimental atherosclerosis. We have shown previously that exposure to sidestream cigarette smoke (SSCS) enhances atherosclerotic lesion formation in apoE-deficient mice. The aim of the present study was to determine if CoQ10 protected against SSCS-mediated atherosclerosis. Female apoE-deficient mice were fed a saturated fat-enriched diet (SFD) alone, or supplemented with 1% wt/wt coenzyme Q10 (SFD-Q10). Mice in each diet group were exposed to SSCS for 4hrs/day, 5days/week in a whole-body exposure chamber maintained at 35+/-4mg smoke particulates/m(3). Mice kept in filtered ambient air served as controls. Mice were euthanized after either 6 or 15weeks of SSCS exposure and following measurements were performed: i) lung 7-ethoxyresorufin-O-deethylase (EROD) activity; ii) plasma cholesterol and CoQ10 concentrations; iii) aortic intimal area covered by atherosclerotic lesions; and, iv) pathological characterization of lesions. Lung EROD activity increased in SSCS mice of both diet groups, confirming SSCS exposure. Plasma concentrations of CoQ10 in SFD-Q10-fed mice were increased markedly in comparison to SFD-fed mice. Plasma cholesterol concentrations and distributions of cholesterol in lipoprotein fractions were unaffected by SSCS exposure. Dietary supplementation with CoQ10 significantly reduced atherosclerotic lesions in control mice. As reported previously, exposure to SSCS increased the size of lesions in apoE-/- mice at both time points. However, dietary supplementation with CoQ10 had no effect on atherosclerotic lesions augmented by SSCS exposure. The results suggest a role of oxidative processes in smoke-augmented atherosclerosis that are different than those mitigated by CoQ10.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Cholesterol; Cytochrome P-450 CYP1A1; Diet; Disease Models, Animal; Female; Lung; Mice; Smoke; Ubiquinone

Previous studies of the effects of coenzyme Q10 and minocycline on mouse models of Huntington's disease have produced conflicting results regarding their efficacy in behavioral tests. Using our recently published best practices for husbandry and testing for mouse models of Huntington's disease, we report that neither coenzyme Q10 nor minocycline had significant beneficial effects on measures of motor function, general health (open field, rotarod, grip strength, rearing-climbing, body weight and survival) in the R6/2 mouse model. The higher doses of minocycline, on the contrary, reduced survival. We were thus unable to confirm the previously reported benefits for these two drugs, and we discuss potential reasons for these discrepancies, such as the effects of husbandry and nutrition.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Body Weight; Disease Models, Animal; Female; Hand Strength; Huntington Disease; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Minocycline; Motor Skills; Ubiquinone

The CHDI Fifth Annual HD Therapeutics Conference, held in Palm Springs, CA, included topics covering new therapeutic developments in the field of Huntington's disease (HD). This conference report highlights presentations on biomarkers in HD; emerging topics in drug targeting, such as the lysosomal degradation pathway and target prediction by network-based modeling; understanding phenotype and neuronal circuit dysfunction in animal models; regulation of huntingtin protein expression and function; RNAi and antisense technology to deplete the mutant huntingtin protein; and small-molecule drugs that are progressing quickly through the clinic. Investigational drugs discussed include ALN-HTT (Alnylam Pharmaceuticals Inc/Medtronic Inc), EPI-743 (Edison Pharmaceuticals Inc), LNK-754 (Link Medicine Corp) and pridopidine (NeuroSearch A/S).

Topics: Animals; Biomarkers; Disease Models, Animal; Dopamine; Drug Delivery Systems; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Huntingtin Protein; Huntington Disease; Leigh Disease; Lysosomes; Models, Biological; Nerve Tissue Proteins; Neurodegenerative Diseases; Nuclear Proteins; Oligonucleotides, Antisense; Phosphorylation; Piperidines; RNA, Small Interfering; Sheep; Sirtuin 1; Ubiquinone

Krabbe disease or globoid cell leukodystrophy is an autosomal recessively inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme that catalyzes the hydrolysis of galactose from galactosylceramide and galactosylsphingosine (psychosine). Psychosine accumulation results in the loss of myelin and oligodendrocytes in the brain of Krabbe patients as well as twitcher mice (natural model of human Krabbe disease). The aim of the present research was to investigate in twitcher mice the potential role of a diet deficient in galactose enriched in soy isoflavones and a pool of antioxidants molecules, such as l-glutathione, coenzyme Q10, xanthophylls, in counteracting the toxic effects derived by psychosine accumulation. A second goal of this manuscript was to demonstrate suppression of the apoptotic effects of psychosine in cultured oligodendrocyte progenitor mice cells (OLP-II) with antioxidants. The affected twitcher mice began the milk-derivatives free diet on post-natal day 15 although they also received mother's milk until post-natal day 18. Nevertheless, average life span was increased 50%, from 32+/-2 to 48+/-3 days, onset of tremor was delayed 17 days (from 21 days in the untreated twitcher mice to 38 days in the treated affected mice) and the gait in the treated mice was normal until almost a week after the untreated animals died (38+/-1 days versus 32 days at death). Weight gain in the treated animals also progressed to 38 days compared with 22 days for the untreated affected twitcher mice. Protection of the OLP-II cells against psychosine was shown using the MTT test (the ability of the tetrazolium salt MTT to form a dark blue formazan product by mitochondrial dehydrogenase in viable cells) and assay of expression of p53 and TNF-related apoptosis-inducing ligand (TRAIL). The results showed a time-dependent and concentration-dependent decrease of OLP-II viability on exposure to psychosine and dose-dependent protection with the antioxidants xanthophylls and glutathione. They also demonstrated that psychosine-induced p53 induction of apoptosis and TNF-related apoptosis-inducing ligand receptors could be decreased by l-glutathione and xanthophylls. A dietary approach may constitute a promising clinical management of the late-infantile and juvenile forms of Krabbe leukodystrophy.

Topics: Animals; Antioxidants; Apoptosis; Cell Survival; Cells, Cultured; Disease Models, Animal; Female; Galactose; Glutathione; Humans; Isoflavones; Leukodystrophy, Globoid Cell; Male; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Oligodendroglia; Psychosine; Ubiquinone; Xanthophylls

This study tests the hypothesis that statins (HMGCoA reductase inhibitors) inhibit carcinogenesis and that this effect may be mediated by the statin-induced inhibition of ubiquinone synthesis.. The effects of lovastatin, with and without addition of ubiquinone, were studied in a rat model for chemically induced hepatocarcinogenesis. Intermediates in the mevalonate pathway were measured.. Lovastatin treatment reduced the volume fraction of liver nodules by 50% and the cell proliferation within the liver nodules was reduced to one third. Ubiquinone (Q10) treatment reversed the statin-induced inhibition of cell proliferation. Lathosterol levels were reduced significantly in the statin-treated rats, indicating inhibition of the mevalonate pathway, but cholesterol levels were not affected.. Lovastatin inhibits carcinogenesis in a rat model for liver cancer, despite unaffected cholesterol levels. The statin-induced inhibition of cell proliferation may, at least in part, be explained by the inhibition of ubiquinone synthesis.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Body Weight; Cell Growth Processes; Cholesterol; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Liver Neoplasms, Experimental; Lovastatin; Male; Mevalonic Acid; Organ Size; Precancerous Conditions; Rats; Rats, Inbred F344; Ubiquinone

Ischaemia-reperfusion injury is a life-threatening complication of lung transplantation. Attempts to ameliorate this injury have included optimization of donor management and improving techniques of lung preservation. However, few investigators have sought to pretreat potential recipients. Coenzyme Q(10) (CoQ(10)) is a potent antioxidant and cellular energizer that has been shown to protect the heart against injury. However, its protective effect in the lung is unknown. We therefore set out to study the impact of Coenzyme Q(10) pretreatment in a model of mild and severe lung injury.. We evaluated the impact of CoQ(10) in a two-stage laboratory study. In the first stage, in order to measure the magnitude of increase in tissue and plasma CoQ(10) following oral therapy we administered high-dose oral CoQ(10) to rats (n = 6). In the second stage we evaluated the impact of CoQ(10) in the rat lung (n = 10) that was subjected to 230 min of normoxic lung injury or 90 min of warm ischaemia and 120 min of reperfusion in a model of lung transplantation.. High-dose oral CoQ(10) for 7 days produced a 15-fold increase in plasma and a 3-fold increase in lung CoQ(10). In the normoxic lung, the injury-induced rise in peak airway pressure was reduced by CoQ(10) treatment at 90 min (P = 0.037) and at 120 min (P = 0.005) without any change in arterial oxygen. In the lung subjected to severe ischaemia-reperfusion injury, CoQ(10) did not reduce the injury-induced increase in peak airway pressure (P = 0.599) nor the decrease in arterial oxygen (P = 0.844). However, CoQ(10) markedly reduced the increase in tumour necrosis factor-alpha in ischaemic compared with normoxic lung (P = 0.027).. The effect of CoQ(10) pretreatment is insufficient to protect the lung against severe ischaemia-reperfusion as may occur in lung transplantation. However, in the setting of less severe pulmonary injury as in anaesthesia and non-transplant surgery, CoQ(10) may have a protective role.

Topics: Administration, Oral; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Lung; Lung Injury; Lung Transplantation; Male; Protective Agents; Rats; Reference Values; Reperfusion Injury; Treatment Outcome; Ubiquinone

Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory chain component, oxidized coenzyme Q9 ((ox)CoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, high-fat (HF), or high-fat high-carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water, whereas the HFHC group received water with 55% fructose and 45% sucrose (wt/vol). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin-resistant compared with chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma alanine aminotransferase, and liver weight were significantly increased in HF and HFHC mice compared with chow mice. Plasma cholesterol (P < 0.001), histological hepatic fibrosis, liver hydroxyproline content (P = 0.006), collagen 1 messenger RNA (P = 0.003), CD11b-F4/80+Gr1+ monocytes (P < 0.0001), transforming growth factor beta1 mRNA (P = 0.04), and alpha-smooth muscle actin messenger RNA (P = 0.001) levels were significantly increased in HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression (P = 0.002), 4-hydroxynonenal, and plasma (ox)CoQ9 (P < 0.001) levels, was highest in HFHC mice.. These findings demonstrate that nongenetically modified mice maintained on an HFHC diet in addition to developing obesity have increased hepatic ROS and a NASH-like phenotype with significant fibrosis. Plasma (ox)CoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation, resulting in transforming growth factor beta1-signaled collagen deposition and histologically visible hepatic fibrosis.

Topics: Animals; Body Composition; Collagen; Dietary Carbohydrates; Dietary Fats; Disease Models, Animal; Fatty Liver; Fructose; Insulin Resistance; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Obesity; Reactive Oxygen Species; Trans Fatty Acids; Transforming Growth Factor beta; Ubiquinone

Evidence exists that nitric oxide (NO) may mediate both protective and pathological responses during brain hypoxia (HP). Reactive oxygen species have also been implicated in the pathophysiological response of the brain tissues to HP. Therefore, this study investigated whether a NO precursor, l-arginine (l-arg), a free radical scavenger, idebenone (ID), and their combination would reduce neurological injury resulting from hemic hypoxia (HP) in rats. Adult male Wistar albino rats were injected with sodium nitrite (60 mg/kg, s.c.) to establish hemic hypoxia. ID (100 mg kg(-1), i.p.) and/or l-arg (100 mg kg(-1), i.p.) were administrated 24 and 1h prior to sodium nitrite intoxication, respectively. Hypoxia significantly decreased hemoglobin concentration, while significantly increased serum lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total nitrate/nitrite, sialic, and uric acids concentrations. Moreover, brain lipid peroxides were significantly enhanced, while reduced glutathione, l-ascorbic acids, adenosine triphosphate (ATP) contents, and the activities of catalase and superoxide dismutase, were significantly reduced in the brain tissue. Pretreatment with either ID or l-arg altered the majority of the above-mentioned biochemical changes in hypoxic rats. Additionally, the combination of these two agents significantly reduced injury marker enzyme activities as well as serum sialic, and uric acids level (P>0.05 vs. control). Moreover, this combination exerted a synergistic antioxidant effect by blocking the induction of lipid peroxidation, preserving brain energy (ATP) content, and greatly reducing the hypoxic alterations in brain enzymatic and non-enzymatic antioxidants. Histopathological examination of the brain tissue supported these biochemical findings. This study showed that ID and l-arg were capable of reducing neurological injury following HP in rat, and support the idea of the usefulness of l-arg and ID as prophylaxis from hypoxic brain injury.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Arginine; Brain; Catalase; Creatine Kinase; Disease Models, Animal; Drug Administration Schedule; Drug Combinations; Gliosis; Hemoglobins; Hypoxia, Brain; L-Lactate Dehydrogenase; Male; Nervous System Diseases; Neurons; Nitrates; Nitric Oxide; Random Allocation; Rats; Rats, Wistar; Superoxide Dismutase; Time Factors; Ubiquinone

The objective of this study was to assess the neuroprotective effects of a mitochondria-targeted antioxidant, Mito-Q(10), the coenzyme-Q analog attached to a triphenylphosphonium cation that targets the antioxidant to mitochondria, in experimental models of Parkinson's disease (PD). Primary mesencephalic neuronal cells and cultured dopaminergic cells were treated with 1-methyl-4-phenylpyridinium (MPP(+)), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and mice were used for testing the efficacy of Mito-Q(10). MPP(+) treatment caused a dose-dependent loss of tyrosine hydroxylase and membrane potential and an increase in caspase-3 activation in dopaminergic cells, which were reversed by Mito-Q(10). MPTP treatment induced a loss of striatal dopamine and its metabolites, inactivation of mitochondrial aconitase in the substantia nigra, and a loss of locomotor activity in mice. Treatment with Mito-Q(10) significantly inhibited both MPP(+)- and MPTP-induced neurotoxicity in cell culture and mouse models. Collectively, these results indicate that mitochondrial targeting of antioxidants is a promising neuroprotective strategy in this preclinical mouse model of PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cells, Cultured; Cytoprotection; Disease Models, Animal; Dopamine; Drug Delivery Systems; Drug Evaluation, Preclinical; Male; Mice; Mitochondria; Neurons; Neuroprotective Agents; Neurotoxins; Organophosphorus Compounds; Osmolar Concentration; Parkinsonian Disorders; Rats; Ubiquinone

Topics: Animals; Biomarkers; Disease Models, Animal; Dogs; Fluorobenzenes; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Ubiquinone

The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS) also in noise induced hearing loss (NIHL) and anti-oxidants and free-radicals scavengers have been shown to attenuate the damage. Coenzyme Q(10) (CoQ(10)) or ubiquinone has a bioenergetic role as a component of the mithocondrial respiratory chain, it inhibits mitochondrial lipid peroxidation, inducing ATP production and it is involved in ROS removal and prevention of oxidative stress-induced apoptosis. However the therapeutic application of CoQ(10) is limited by the lack of solubility and poor bio- availability, therefore it is a challenge to improve its water solubility in order to ameliorate the efficacy in tissues and fluids. This study was conducted in a model of acoustic trauma in the guinea pig where the effectiveness of CoQ(10) was compared with a soluble formulation of CoQ(10) (multicomposite CoQ(10) Terclatrate, Q-ter) given intraperitoneally 1 h before and once daily for 3 days after pure tone noise exposure (6 kHz for 1 h at 120 dB SPL). Functional and morphological studies were carried out by measuring auditory brainstem responses, scanning electron microscopy for hair cell loss count, active caspase 3 staining and terminal deoxynucleotidyl transferase-mediated dUTP labelling assay in order to identify initial signs of apoptosis. Treatments decreased active caspase 3 expression and the number of apoptotic cells, but animals injected with Q-ter showed a greater degree of activity in preventing apoptosis and thus in improving hearing. These data confirm that solubility of Coenzyme Q(10) improves the ability of CoQ(10) in preventing oxidative injuries that result from mitochondrial dysfunction.

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Apoptosis; Auditory Threshold; Caspase 3; Cell Count; Disease Models, Animal; Guinea Pigs; Hair Cells, Auditory, Outer; Hearing Loss, Noise-Induced; In Situ Nick-End Labeling; Microscopy, Confocal; Microscopy, Electron, Scanning; Solubility; Ubiquinone; Water

One cellular consequence of status epilepticus is apoptosis in the hippocampal CA3 subfield. We evaluated the hypothesis that the repertoire of cellular events that underlie such elicited cell death entails mitochondrial dysfunction induced by an excessive production of nitric oxide synthase II (NOS II)-derived NO, increased superoxide anion (O(2)(-)) production, and peroxynitrite formation.. In Sprague-Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure-like electroencephalography (EEG) activity. The effects of pretreatments with various test agents on the induced O(2)(-) production, peroxynitrite formation, mitochondrial respiratory chain enzyme activities, cytochrome c/caspase-3 signaling, and DNA fragmentation in bilateral CA3 subfields were examined.. Significantly and temporally correlated increase in O(2)(-) and peroxynitrite levels (3 to 24 h), depressed mitochondrial Complex I activity (3 h), enhanced translocation of cytochrome c to cytosol (day 1), and augmented activated caspase-3 (day 7) and DNA fragmentation (day 7) were detected bilaterally in hippocampal CA3 subfields after the elicitation of sustained seizure. Pretreatment with microinjection into the bilateral hippocampal CA3 subfield of a water-soluble formulation of coenzyme Q(10); a selective NOS II inhibitor, S-methylisothiourea; a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; an active peroxynitrite decomposition catalyst, 5,10, 15,20-tetrakis-(N-methyl-4-pyridyl)- porphyrinato iron (III); or a peroxynitrite scavenger, L-cysteine significantly blunted these cellular events.. Prolonged seizures prompted NO-, O(2)(-)-, and peroxynitrite-dependent reduction in mitochondrial respiratory enzyme Complex I activity, leading to cytochrome c/caspase-3-dependent apoptotic cell death in the hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus.

Topics: Analysis of Variance; Animals; Apoptosis; Caspase 3; Disease Models, Animal; DNA Fragmentation; Electroencephalography; Electron Transport Complex III; Enzyme Activation; Enzyme Inhibitors; Epilepsy, Temporal Lobe; Hippocampus; Kainic Acid; Male; Mitochondria; NAD; Nitric Oxide; Peroxynitrous Acid; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Signal Transduction; Superoxides; Time Factors; Ubiquinone

Coenzyme Q(10) (CoQ(10)) and creatine are promising agents for neuroprotection in neurodegenerative diseases via their effects on improving mitochondrial function and cellular bioenergetics and their properties as antioxidants. We examined whether a combination of CoQ(10) with creatine can exert additive neuroprotective effects in a MPTP mouse model of Parkinson's disease, a 3-NP rat model of Huntington's disease (HD) and the R6/2 transgenic mouse model of HD. The combination of the two agents produced additive neuroprotective effects against dopamine depletion in the striatum and loss of tyrosine hydroxylase neurons in the substantia nigra pars compacta (SNpc) following chronic subcutaneous administration of MPTP. The combination treatment resulted in significant reduction in lipid peroxidation and pathologic alpha-synuclein accumulation in the SNpc neurons of the MPTP-treated mice. We also observed additive neuroprotective effects in reducing striatal lesion volumes produced by chronic subcutaneous administration of 3-NP to rats. The combination treatment showed significant effects on blocking 3-NP-induced impairment of glutathione homeostasis and reducing lipid peroxidation and DNA oxidative damage in the striatum. Lastly, the combination of CoQ(10) and creatine produced additive neuroprotective effects on improving motor performance and extending survival in the transgenic R6/2 HD mice. These findings suggest that combination therapy using CoQ(10) and creatine may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease and HD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 8-Hydroxy-2'-Deoxyguanosine; alpha-Synuclein; Analysis of Variance; Animals; Chromatography, High Pressure Liquid; Creatine; Deoxyguanosine; Disease Models, Animal; Dopamine; Drug Therapy, Combination; Glutathione; Glutathione Disulfide; Huntington Disease; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Nitro Compounds; Parkinson Disease; Propionates; Rats; Rats, Inbred Lew; Tyrosine 3-Monooxygenase; Ubiquinone

We recently reported insulin resistance in adult offspring of obese C57BL/6J mice. We have now evaluated whether parameters of skeletal muscle structure and function may play a role in insulin resistance in this model of developmental programming. Obesity was induced in female mice by feeding a highly palatable sugar and fat-rich diet for 6 wk prior to pregnancy, and during pregnancy and lactation. Offspring of obese dams were weaned onto standard laboratory chow. At 3 mo of age, skeletal muscle insulin signaling protein expression, mitochondrial electron transport chain activity (ETC), muscle fiber type, fiber density, and fiber cross-sectional area were compared with that of offspring of control dams weaned onto the chow diet. Female offspring of obese dams demonstrated decreased skeletal muscle expression of p110beta, the catalytic subunit of PI3K (P < 0.01), as well as reduced Akt phosphorylation at Serine residue 473 compared with control offspring. Male offspring of obese dams demonstrated increased skeletal muscle Akt2 and PKCzeta expression (P < 0.01; P < 0.001, respectively). A decrease in mitochondrial-linked complex II-III was observed in male offspring of obese dams (P < 0.01), which was unrelated to CoQ deficiency. This was not observed in females. There were no differences in muscle fiber density between offspring of obese dams and control offspring in either sex. Sex-related alterations in key insulin-signaling proteins and in mitochondrial ETC may contribute to a state of insulin resistance in offspring of obese mice.

Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Electron Transport Complex II; Electron Transport Complex III; Female; Glucose Transporter Type 4; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred C57BL; Mitochondria, Muscle; Muscle Fibers, Skeletal; Obesity; Phosphatidylinositol 3-Kinases; Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Protein Kinase C; Proto-Oncogene Proteins c-akt; Quadriceps Muscle; Receptor, Insulin; Sex Factors; Signal Transduction; Ubiquinone

Cardiovascular alterations and periodontal disease have been associated, although cardiovascular disease treatments have not yet been tested against periodontal alterations. We investigated effects of squalene, hydroxytyrosol and coenzyme Q(10) on gingival tissues of rabbits fed on an atherosclerotic diet. Forty-eight rabbits were distributed in six groups. Control group was fed on standard chow for 80 days. The rest were fed with an atherogenic diet for 50 days. After that, a group was sacrificed and the rest were subjected for another extra 30 days on commercial chow alone or supplemented with coenzyme Q(10), squalene or hydroxytyrosol. Atherosclerotic rabbits had higher fibrosis and endothelial activation and lower cellularity in gingival mucosa than controls (P<0.05). Hydroxytyrosol reduced endothelial activation (P<0.05) and squalene additionally decreased fibrosis (P<0.05). Results suggest that gingival vascular changes after the atherosclerotic diet have been reversed by hydroxytyrosol and squalene, natural products from the minor fraction of virgin olive oil.

Topics: Animals; Antioxidants; Arteries; Atherosclerosis; Collagen; Diet, Atherogenic; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Fibrosis; Gingiva; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mouth Mucosa; Olive Oil; Periodontal Diseases; Phenylethyl Alcohol; Plant Oils; Rabbits; Squalene; Ubiquinone

Mitochondria are a major site of reactive oxygen species production, which may contribute to the development of cardiovascular disease. Protecting mitochondria from oxidative damage should be an effective therapeutic strategy; however, conventional antioxidants are ineffective, because they cannot penetrate the mitochondria. This study investigated the role of mitochondrial oxidative stress during development of hypertension in the stroke-prone spontaneously hypertensive rat, using the mitochondria-targeted antioxidant, MitoQ(10). Eight-week-old male stroke-prone spontaneously hypertensive rats were treated with MitoQ(10) (500 mumol/L; n=16), control compound decyltriphenylphosphonium (decylTPP; 500 mumol/L; n=8), or vehicle (n=9) in drinking water for 8 weeks. Systolic blood pressure was significantly reduced by approximately 25 mm Hg over the 8-week MitoQ(10) treatment period compared with decylTPP (F=5.94; P=0.029) or untreated controls (F=65.6; P=0.0001). MitoQ(10) treatment significantly improved thoracic aorta NO bioavailability (1.16+/-0.03 g/g; P=0.002, area under the curve) compared with both untreated controls (0.68+/-0.02 g/g) and decylTPP-treated rats (0.60+/-0.06 g/g). Cardiac hypertrophy was significantly reduced by MitoQ(10) treatment compared with untreated control and decylTPP treatment (MitoQ(10): 4.01+/-0.05 mg/g; control: 4.42+/-0.11 mg/g; and decylTPP: 4.40+/-0.09 mg/g; ANOVA P=0.002). Total MitoQ(10) content was measured in liver, heart, carotid artery, and kidney harvested from MitoQ(10)-treated rats by liquid chromatography-tandem mass spectrometry. All of the organs analyzed demonstrated detectable levels of MitoQ(10), with comparable accumulation in vascular and cardiac tissues. Administration of the mitochondria-targeted antioxidant MitoQ(10) protects against the development of hypertension, improves endothelial function, and reduces cardiac hypertrophy in young stroke-prone spontaneously hypertensive rats. MitoQ(10) provides a novel approach to attenuate mitochondrial-specific oxidative damage with the potential to become a new therapeutic intervention in human cardiovascular disease.

Topics: Analysis of Variance; Animals; Antioxidants; Blood Pressure; Cardiomegaly; Disease Models, Animal; Drug Delivery Systems; Endothelium, Vascular; Hypertension; Male; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Probability; Random Allocation; Rats; Rats, Inbred SHR; Risk Factors; Sensitivity and Specificity; Ubiquinone

Fluorides, when taken in amounts exceeding the standard therapeutic dosage, are regarded as toxic substances. Recent studies show that fluorides may affect the oxidoreductive processes of cells. The aim of the following study is to investigate the effect of antioxidative vitamins A and E and coenzyme Q on the morphological picture of the lungs and pancreata of rats exposed to high doses of sodium fluoride. The study was performed on 18 female rats, which were divided into 3 groups: a control group and 2 experimental groups. The control group received distilled water and standard fodder. Experimental groups I and II both received sodium fluoride (2.5mg/rat/24h). In addition, animals in group II received vitamin A (250 IU/rat/24h), vitamin E (3mg/rat/24h), and coenzyme Q (200 microg/rat/24h). The experiment was conducted for a period of 35 days. Upon dissection, lungs and pancreata were taken for histopathological examination. Pathomorphological evaluations of the removed organs were performed using paraffin preparations, stained with hematoxylin and eosin. The aldolase activity in the pancreata was measured using colorimetric methods and the protein concentration by the Lowry method. In the case of group I, pathomorphological examinations of the lungs revealed the appearance of erythrorrhagia, hyperaemia, necrosis of epithelium cells, numerous macrophages in interalveolar septa, infiltrations in the area of blood vessels and emphysematous blebs. Focal vacuolar degeneration cells and inflammatory infiltrations appeared only in pancreata. The results confirmed that the administration of vitamins A and E and coenzyme Q has a counteracting influence upon the degenerative changes seen in the examined organs.

Topics: Animals; Antioxidants; Disease Models, Animal; Drug Therapy, Combination; Female; Fructose-Bisphosphate Aldolase; Lung; Micronutrients; Oxidative Stress; Pancreas; Rats; Rats, Wistar; Sodium Fluoride; Ubiquinone; Vitamin A; Vitamin E

Sepsis elicits severe alterations in cardiac function, impairing cardiac mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced cardiac dysfunction. We tested the hypothesis that administration of a mitochondrially targeted antioxidant, 10-(6'-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), would prevent endotoxin-induced reductions in cardiac mitochondrial and contractile function. Studies were performed on adult rodents (n = 52) given either saline, endotoxin (8 mg x kg(-1) x day(-1)), saline + MitoQ (500 microM), or both endotoxin and MitoQ. At 48 h animals were killed and hearts were removed for determination of either cardiac mitochondrial function (using polarography) or cardiac pressure generation (using the Langendorf technique). We found that endotoxin induced reductions in mitochondrial state 3 respiration rates, the respiratory control ratio, and ATP generation. Moreover, MitoQ administration prevented each of these endotoxin-induced abnormalities, P < 0.001. We also found that endotoxin produced reductions in cardiac pressure-generating capacity, reducing the systolic pressure-diastolic relationship. MitoQ also prevented endotoxin-induced reductions in cardiac pressure generation, P < 0.01. One potential link between mitochondrial and contractile dysfunction is caspase activation; we found that endotoxin increased cardiac levels of active caspases 9 and 3 (P < 0.001), while MitoQ prevented this increase (P < 0.01). These data demonstrate that MitoQ is a potent inhibitor of endotoxin-induced mitochondrial and cardiac abnormalities. We speculate that this agent may prove a novel therapy for sepsis-induced cardiac dysfunction.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Caspase 3; Caspase 9; Cell Respiration; Disease Models, Animal; Drug Administration Schedule; Endotoxemia; Enzyme Activation; Heart Diseases; Mice; Mitochondria, Heart; Myocardial Contraction; Myocardium; Organophosphorus Compounds; Protein Carbonylation; Rats; Tumor Necrosis Factor-alpha; Ubiquinone; Ventricular Function, Left; Ventricular Pressure

This work aimed to assess some pharmacological activities of coenzyme Q(10) (CoQ(10)) in animal experimental models.. The chick chorioallantoic membrane assay was used to evaluate anti-angiogenic activity of CoQ(10). Anti-inflammatory activity of CoQ(10) was confirmed using two animal models of inflammation. These were the vascular permeability and air pouch models, models of acute and sub-acute inflammation, respectively. Antinociceptive activity was assessed by the acetic acid-induced abdominal constriction response.. CoQ(10) dose-dependently displayed inhibition of chick chorioallantoic membrane angiogenesis. In the acetic acid-induced vascular permeability model in mice, CoQ(10) at 50, 100 and 200 mg/kg reduced vascular permeability from 0.74 +/- 0.01 (A(590)) to 0.67 +/- 0.01 (P < 0.01), 0.46 +/- 0.02 (P < 0.01) and 0.30 +/- 0.01 (P < 0.01), respectively. In the carrageenan-induced inflammation in the air pouch, CoQ(10) was able to diminish exudate volume, the number of polymorphonulcear leucocytes and nitrite content in the air pouches. CoQ(10) at 25, 50 and 100 mg/kg significantly reduced acetic acid-induced abdominal constriction in mice from 27.0 +/- 2.00 (number of abdominal constrictions) to 17.7 +/- 0.33 (P < 0.01), 9.3 +/- 0.67 (P < 0.01) and 1.3 +/- 0.33 (P < 0.01), respectively, suggesting a strong antinociceptive activity.. CoQ(10) possessed considerable anti-angiogenic, anti-inflammatory and antinociceptive activity, possibly via down-regulating the level of nitric oxide, which partly supported its use as a dietary supplement and in combination therapy.

Topics: Abdominal Pain; Analgesics; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Capillary Permeability; Chick Embryo; Chorioallantoic Membrane; Disease Models, Animal; Dose-Response Relationship, Drug; Exudates and Transudates; Inflammation; Male; Mice; Mice, Inbred ICR; Neovascularization, Physiologic; Nitrites; Ubiquinone; Vitamins

Diabetes-induced injury related to hyperglycaemia is associated with impaired function of mitochondria. Regardless of their cytotoxicity, PAMAM [poly(amido)amine] G4 dendrimers lower plasma glucose and suppress long-term markers of diabetic hyperglycaemia in experimental diabetes. In the present study, we aimed at verifying whether such modulatory effects of PAMAM G4 (0.5 micromol/kg of body weight daily for 60 days) may contribute to improved respiration in heart and liver mitochondria from streptozotocin-diabetic rats. PAMAM G4 alleviated long-term markers of hyperglycaemia and reduced blood and tissue lipophilic antioxidants in diabetic animals, but did not restore mitochondrial function. In hearts, but not livers, dendrimers further reduced respiratory function and oxidative phosphorylation. Thus ameliorating effects of PAMAM G4 on glycation and glycoxidation in experimental diabetes are not sufficient to restore the impaired mitochondrial function in diabetes.

Topics: Animals; Antioxidants; Blood Glucose; Dendrimers; Diabetes Mellitus, Experimental; Disease Models, Animal; Male; Mitochondria, Heart; Mitochondria, Liver; Nylons; Oxidative Phosphorylation; Rats; Rats, Wistar; Tocopherols; Ubiquinone

Metabolic syndrome (MetS) is a group of cardiovascular risk factors, including visceral obesity, glucose intolerance, hypertension, and dyslipidemia. Increased oxidative and nitrative stress and inflammation and decreased endothelial function occur in an animal model of metabolic syndrome, SHR/NDmcr-cp (SHR/cp) rats. The present study investigated the effects of coenzyme Q10 (CoQ10), one of the important antioxidants, on the abnormal oxidative condition and characteristic components of metabolic syndrome in SHR/cp rats by maintaining them on a diet supplemented with 0.07% - 0.7% CoQ10 for 26 weeks. We determined serum levels of oxidatively modified low-density lipoprotein (Ox-LDL) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as oxidative stress markers, 3-nitrotyrosine as a nitrative stress marker, 3-chlorotyrosine as a marker of myeloperoxidase (MPO)-catalyzed oxidation and high-sensitivity C-reactive protein (hsCRP) as an inflammatory marker. The administration of CoQ10 significantly attenuated the increase of oxidative and nitrative stress markers and inflammatory markers in a dose-dependent manner. CoQ10 prevented the elevated serum insulin levels, although it did not affect the elevated glucose level and dyslipidemia. CoQ10 also reduced elevated blood pressure, but did not affect body weight gain. In addition, CoQ10 improved endothelial dysfunction in the mesenteric arteries. These findings suggest that the antioxidant properties of CoQ10 can be effective for ameliorating cardiovascular risk in MetS.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Body Weight; Deoxyguanosine; Disease Models, Animal; Inflammation; Insulin; Lipids; Lipoproteins, LDL; Metabolic Syndrome; Oxidative Stress; Peroxidase; Rats; Rats, Inbred SHR; Tyrosine; Ubiquinone

Inhibition of squalene synthesis could transform unstable, macrophage/lipid-rich coronary plaques into stable, fibromuscular plaques. We have here treated WHHLMI rabbits, a model for coronary atherosclerosis and myocardial infarction, with a novel squalene synthase inhibitor, lapaquistat acetate (TAK-475).. Young male WHHLMI rabbits were fed a diet supplemented with lapaquistat acetate (100 or 200 mg per kg body weight per day) for 32 weeks. Serum lipid levels were monitored every 4 weeks. After the treatment, lipoprotein lipid and coenzyme Q10 levels were assayed, and coronary atherosclerosis and xanthomas were examined histopathologically or immunohistochemically. From histopathological and immunohistochemical sections, the composition of the plaque was analysed quantitatively with computer-assisted image analysis. Xanthoma was evaluated grossly.. Lapaquistat acetate decreased plasma cholesterol and triglyceride levels, by lowering lipoproteins containing apoB100. Development of atherosclerosis and xanthomatosis was suppressed. Accumulation of oxidized lipoproteins, macrophages and extracellular lipid was decreased in coronary plaques of treated animals. Treatment with lapaquistat acetate increased collagen concentration and transformed coronary plaques into fibromuscular plaques. Lapaquistat acetate also suppressed the expression of matrix metalloproteinase-1 and plasminogen activator inhibitor-1 in the plaque and increased peripheral coenzyme Q10 levels. Increased coenzyme Q10 levels and decreased very low-density lipoprotein cholesterol levels were correlated with improvement of coronary plaque composition.. Inhibition of squalene synthase by lapaquistat acetate delayed progression of coronary atherosclerosis and changed coronary atheromatous plaques from unstable, macrophage/lipid accumulation-rich, lesions to stable fibromuscular lesions.

Topics: Animals; Apolipoprotein B-100; Cholesterol; Collagen; Coronary Artery Disease; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Hypercholesterolemia; Hypolipidemic Agents; Image Interpretation, Computer-Assisted; Immunohistochemistry; Lipid Metabolism; Lipoproteins, LDL; Macrophages; Male; Matrix Metalloproteinase 1; Oxazepines; Piperidines; Plasminogen Activator Inhibitor 1; Rabbits; Triglycerides; Ubiquinone; Xanthomatosis

Schistosoma mansoni (S. mansoni) eggs trapped in the host liver elicit a chain of oxidative processes that may be, at least in part, responsible for the pathology and progression of fibrosis associated with schistosomal hepatitis. This study was designed to assess the protective effect of the antioxidant coenzyme-Q10 (Co-Q10) against experimental S. mansoni-induced oxidative stress in the liver, and its potential role as an adjuvant to praziquantel (PZQ) therapy. The oxidative stress and overall liver function were improved under Co-Q10 therapy as evidenced by significant reduction in oxidative stress markers and preservation of antioxidant factors. Liver fibrosis was also reduced with a positive impact on liver function. Moreover, addition of Co-Q10 to PZQ therapy caused: significant reduction of liver egg load, significant improvement of the redox status, and lastly decreased liver fibrosis.

Topics: Actins; Animals; Anthelmintics; Aryldialkylphosphatase; Biomphalaria; Carboxylic Ester Hydrolases; Disease Models, Animal; Glutathione; Hepatitis; Immunohistochemistry; Liver; Liver Diseases, Parasitic; Male; Malondialdehyde; Mice; Nitric Oxide; Oxidative Stress; Parasite Egg Count; Praziquantel; Schistosomiasis mansoni; Specific Pathogen-Free Organisms; Ubiquinone

The objective was to evaluate the pulmonary disposition of the ubiquinone homolog coenzyme Q(1) (CoQ(1)) on passage through lungs of normoxic (exposed to room air) and hyperoxic (exposed to 85% O(2) for 48 h) rats. CoQ(1) or its hydroquinone (CoQ(1)H(2)) was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of CoQ(1)H(2) and CoQ(1) were measured. CoQ(1)H(2) appeared in the venous effluent when CoQ(1) was infused, and CoQ(1) appeared when CoQ(1)H(2) was infused. In normoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 58 and 33% in the presence of rotenone (mitochondrial complex I inhibitor) and dicumarol [NAD(P)H-quinone oxidoreductase 1 (NQO1) inhibitor], respectively. Inhibitor studies also revealed that lung CoQ(1)H(2) oxidation was via mitochondrial complex III. In hyperoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 23% compared with normoxic lungs. Based on inhibitor effects and a kinetic model, the effect of hyperoxia could be attributed predominantly to 47% decrease in the capacity of complex I-mediated CoQ(1) reduction, with no change in the other redox processes. Complex I activity in lung homogenates was also lower for hyperoxic than for normoxic lungs. These studies reveal that lung complexes I and III and NQO1 play a dominant role in determining the vascular concentration and redox status of CoQ(1) during passage through the pulmonary circulation, and that exposure to hyperoxia decreases the overall capacity of the lung to reduce CoQ(1) to CoQ(1)H(2) due to a depression in complex I activity.

Topics: Animals; Disease Models, Animal; Electron Transport Complex I; Electron Transport Complex III; Enzyme Inhibitors; Hyperoxia; Kinetics; Lung; Mitochondria; Models, Cardiovascular; NAD(P)H Dehydrogenase (Quinone); Oxidation-Reduction; Oxidoreductases; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Ubiquinone

We studied the influence of antioxidants (trolox, melatonin and coenzyme Q10) on 6-hydroxydopamine-induced degeneration in the substantia nigra dopaminergic neurons from the left brain hemisphere. In rats, the level of unilateral degeneration of nigrostriatal dopaminergic system was estimated on the base of an intensity of rotation movements which were contralateral to denervated hemishere and resulted from systemic injections of a dopamine receptor agonist apomorphine. It has been shown that all tested antioxidants reduced a number of animals with apomorphine-induced behavioral asymmetry in a different degree: coenzyme Q10 reduced it twofold, trolox - fivefold and melatonin - sevenfold. We suggest that a neuroprotective effects of trolox, melatonin and coenzyme Q10 are associated with their ability to block the mitochondrial pore openings in the nervous cells under exploration, and this is the way to prevent apoptotic death. An oxidative stress has been proved to take part in the apoptosis in dopamine-producing neurons in the substantia nigra, and tested antioxidants have been shown to be effective in preventing neurodegeneration.

Topics: Animals; Antioxidants; Behavior, Animal; Chromans; Disease Models, Animal; Dopamine; Male; Melatonin; Neurons; Oxidative Stress; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Inbred WKY; Substantia Nigra; Ubiquinone

Recent evidence indicates that ischemia and reperfusion are major etiological factors in the bladder dysfunction that occurs after partial bladder outlet obstruction. Coenzyme Q10 and alpha-lipoic acid are found naturally in mitochondria and act as potent antioxidants. We investigated the beneficial effects of coenzyme Q10 plus alpha-lipoic acid in a rabbit model of bladder outlet obstruction.. Twenty male rabbits were divided into 5 groups. Group 1 served as control and group 2 received three weeks of coenzyme Q10 plus alpha-lipoic acid supplementation. Rabbits in group 3 underwent surgical partial bladder outlet obstruction for duration of four weeks and groups 4 and 5 were obstructed for seven weeks. In group 5, coenzyme Q10 plus alpha-lipoic acid supplementation was given following 4 weeks obstruction and continued till the end of the seven weeks. The contractile responses to various agents were determined. The protein nitration and carbonylation levels were studied by immunoblotting. Nerve function was determined by choline acetyltransferase activity and nerve density.. The contractile responses to different forms of stimulations, including field stimulation, ATP, carbachol and KCl all showed decreases following 4 and 7 weeks obstruction. Treatment with coenzyme Q10 plus alpha-lipoic acid significantly restored contractile responses to all forms of stimulation. Treatment also had mitochondrial and neuronal effects and reduced protein nitration and carbonylation. Histologically there was less detrusor muscle hypertrophy.. The current study clearly demonstrates that coenzyme Q10 and alpha-lipoic acid supplementation can improve bladder function after outlet obstruction.

Topics: Analysis of Variance; Animals; Blotting, Western; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Immunohistochemistry; Male; Muscle Contraction; Muscle, Smooth; Probability; Rabbits; Random Allocation; Sensitivity and Specificity; Thioctic Acid; Ubiquinone; Urinary Bladder Neck Obstruction

Current treatment options for parkinsonism as a neurodegenerative disease are limited and still mainly symptomatic and lack significant disease-modifying effect. Understanding its molecular pathology and finding the cause of dopaminergic cell loss will lead to exploring therapies that could prevent and cure the disease. Mitochondrial dysfunction was found to stimulate releasing of reactive oxygen species (ROS) with subsequent induction of apoptotic neuronal cell death. The aim of the present study was to throw the light on the role of coenzyme Q10 with or without L-dopa in an experimental model of parkinsonism induced by rotenone in rats. The present work showed that rotenone (2.5 mg/kg/day i.p. for 60 days) induced a model of parkinsonism (group II) resembling the basic findings in human characterized by bradykinesia and rigidity manifested as an increase in catalepsy score (detected after 20 days with bad prognosis after 60 days) with marked decrease in striatal dopamine levels. This model confirmed the implication of mitochondrial-apoptotic pathway in the pathogenesis of parkinsonism as there was a decrease in levels of striatal complex I activity and ATP as well as extreme overexpression of the antiapoptotic protein Bcl-2, and also exhibited the role of coenzyme Q10 where its plasma and striatal levels were found to be decreased in comparison to the normal control rats (group I). This proposed pathogenesis was evidenced by the significant correlation between catalepsy score and the neurochemical parameters obtained in the current work. The treated groups started to receive the drug(s) after 20 days from induction of parkinsonism and continued to complete for 60 days. Oral administration of Co Q10 in a low dose 200 mg/kg/day (group III) or a high dose 600 mg/kg/day (group IV), resulted in amelioration of the mitochondrial induced apoptosis by dose-dependent restoration of striatal complex I activity, ATP levels with temperate increase in expression of Bcl-2 as well as decrease in catalepsy score. Although both low and high doses of Co Q10 resulted in significant increase in its plasma and striatal levels, but only the high dose was shown to reach the recommended therapeutic levels. As a current replacement therapy, oral administration of levodopa 10 mg/kg/day (group V), caused symptomatic improvement in the form of reduction of catalepsy score with restoration of striatal dopamine levels, but it did not show any significant effects on either striatal c

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Antiparkinson Agents; Behavior, Animal; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Levodopa; Mitochondria; NAD; Neurons; Parkinsonian Disorders; Proto-Oncogene Proteins c-bcl-2; Psychomotor Performance; Rats; Rotenone; Spectrophotometry; Ubiquinone; Ultrasonography; Vitamins

This study was designed to determine whether the supplement of energy compound could attenuate strain-induced damage to skeletal muscle in rats. Energy compound is a saline mixture of the following ingredients: ATP (10mg), Coenzyme-A (50 units), Coenzyme-Q(10) (50mg), Cytochrome C (30 mg) and Vitamin B(6) (50mg). Experimental animals were injured in right gastrocnemius muscles by a strain injury model. Energy compound groups were given energy compound 10 ml/kg body weight per day since injured, while saline groups were given saline at the same dose. And a sham operation was performed on the right hindlimb of control group. Plasma was centrifuged to measure lactate dehydrogenase (LDH), lactic acid (La) and creatine kinase (CK) on 3, 7 and 14 d post injury. Muscles were removed and fixed for histology observation and immunohistochemistry assay of desmin and vimentin. The results showed a similar tendency of plasma CK, La and LDH in saline and energy compound groups, while the lower level was found in the energy-compound group. The histological examination of muscle sections revealed a lower degree of damage in the energy compound group in which the expression levels of desmin and vimentin were higher than in the saline group. It is suggested that energy compound supplement may attenuate strain-induced muscle damage and facilitate its regeneration.

Topics: Adenosine Triphosphate; Animals; Coenzyme A; Cytochromes c; Disease Models, Animal; Energy Metabolism; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Sprains and Strains; Ubiquinone; Vitamin B 6; Wound Healing

Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.

Topics: Animals; Antioxidants; Cell Line; Creatinine; Cytokines; Disease Models, Animal; Endothelial Cells; Humans; Interleukin-10; Lipopolysaccharides; Membrane Potential, Mitochondrial; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Peptidoglycan; Rats; Reactive Oxygen Species; Sepsis; Spectrometry, Fluorescence; Ubiquinone

The importance of nutritional supplementation in diabetes remains an unresolved issue. The present study was undertaken to examine the effects of alpha-tocopherol and CoQ(10), powerful antioxidants, on metabolic control and on the pancreatic mitochondria of GK rats, a model of type 2 diabetes. We also evaluated the efficacy of these nutrients in preventing the diabetic pancreatic lesions observed in GK rats. Rats were divided into 4 groups, a control group of diabetic GK rats and 3 groups of GK rats administered with alpha-tocopherol and CoQ(10) alone or both in association, during 8 weeks. Fasting blood glucose levels were not significantly different between the groups, nor were blood glucose levels at 2 hours after a glucose load. HbA1c level was significantly reduced in the group supplemented with both antioxidants. Diabetes induced a decrease in coenzyme Q plasma levels that prevailed after treatment with antioxidants. In addition, the plasma alpha-tocopherol levels were higher after treatment with the antioxidants. An increment in some components of the antioxidant defense system was observed in pancreatic mitochondria of treated GK rats. Moreover, the antioxidants tested either alone or in association failed to prevent the pancreatic lesions in this animal model of type 2 diabetes. In conclusion, our results indicate that CoQ(10) and alpha-tocopherol decrease glycated HbA1c and pancreatic lipid peroxidation. These antioxidants increase some components of the antioxidant defense system but do not prevent pancreatic lesions. Thus, we cannot rule out the potential benefit of antioxidant treatments in type 2 diabetes in the prevention of their complications.

Topics: alpha-Tocopherol; Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Experimental; Dietary Supplements; Disease Models, Animal; Glucose Tolerance Test; Glycated Hemoglobin; Insulin; Lipid Peroxidation; Male; Pancreas; Random Allocation; Rats; Rats, Inbred Strains; Rats, Wistar; Ubiquinone

Coenzyme Q10 (CoQ10) is a promising agent for neuroprotection in neurodegenerative diseases. We tested the effects of various doses of two formulations of CoQ10 in food and found that administration in the diet resulted in significant protection against loss of dopamine (DA), which was accompanied by a marked increase in plasma concentrations of CoQ10. We further investigated the neuroprotective effects of CoQ10, reduced CoQ10 (ubiquinol), and CoQ10 emulsions in the (MPTP) model of Parkinson's disease (PD). We found neuroprotection against MPTP induced loss of DA using both CoQ10, and reduced CoQ10, which produced the largest increases in plasma concentrations. Lastly, we administered CoQ10 in the diet to test its effects in a chronic MPTP model induced by administration of MPTP by Alzet pump for 1 month. We found neuroprotective effects against DA depletion, loss of tyrosine hydroxylase neurons and induction of alpha-synuclein inclusions in the substantia nigra pars compacta. The finding that CoQ10 is effective in a chronic dosing model of MPTP toxicity, is of particular interest, as this may be more relevant to PD. These results provide further evidence that administration of CoQ10 is a promising therapeutic strategy for the treatment of PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animal Feed; Animals; Coenzymes; Disease Models, Animal; Dopamine; Drug Interactions; Male; Mice; Neurons; Neuroprotective Agents; Neurotoxins; Oxidation-Reduction; Parkinsonian Disorders; Ubiquinone; Vitamins

Statins have been shown to be cardioprotective; however, their interaction with endogenous cardioprotection by ischemic preconditioning and postconditioning is not known. In the present study, we examined if acute and chronic administration of the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor lovastatin affected the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts. Wistar rats were randomly assigned to the following three groups: 1) vehicle (1% methylcellulose per os for 12 days), 2) chronic lovastatin (15 mg.kg(-1).day(-1) per os for 12 days), and 3) acute lovastatin (1% methylcellulose per os for 12 days and 50 micromol/l lovastatin in the perfusate). Hearts isolated from the three groups were either subjected to a nonconditioning (aerobic perfusion followed by 30-min coronary occlusion and 120-min reperfusion, i.e., test ischemia-reperfusion), preconditioning (three intermittent periods of 5-min ischemia-reperfusion cycles before test ischemia-reperfusion), or postconditioning (six cycles of 10-s ischemia-reperfusion after test ischemia) perfusion protocol. Preconditioning and postconditioning significantly decreased infarct size in vehicle-treated hearts. However, preconditioning failed to decrease infarct size in acute lovastatin-treated hearts, but the effect of postconditioning remained unchanged. Chronic lovastatin treatment abolished postconditioning but not preconditioning; however, it decreased infarct size in the nonconditioned group. Myocardial levels of coenzyme Q9 were decreased in both acute and chronic lovastatin-treated rats. Western blot analysis revealed that both acute and chronic lovastatin treatment attenuated the phoshorylation of Akt; however, acute but not chronic lovastatin treatment increased the phosphorylation of p42 MAPK/ERK. We conclude that, although lovastatin may lead to cardioprotection, it interferes with the mechanisms of cardiac adaptation to ischemic stress.

Topics: Animals; Blotting, Western; Disease Models, Animal; Down-Regulation; Drug Administration Schedule; Enzyme Activation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemic Preconditioning, Myocardial; Lovastatin; Male; Mitogen-Activated Protein Kinase 1; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Ubiquinone

Oxidative stress and antioxidants play an important role in neurodegenerative diseases. However, the exact participation of antioxidants in the evolution of prion diseases is still largely unknown. The aim of this study was to assess brain levels of coenzyme Q (CoQ), an endogenous lipophilic antioxidant, and the antioxidant/pro-oxidant status by determining oxidative damage to proteins and lipids after intracerebral bovine spongiform encephalopathy (BSE) infection of transgenic mice expressing bovine prion protein (PrP). Our results indicate that, whereas the ratio between the two CoQ homologues present in mice (CoQ(9) and CoQ(10)) is not altered by prion infection during the course of the disease, significant increases in total CoQ(9) and CoQ(10) were observed in BSE-infected mice 150 days after inoculation. This time point coincided with the first manifestation of PrP(Sc) deposition in nervous tissue. In addition, CoQ(9) and CoQ(10) levels, neuropathological alterations, and PrP(Sc) deposition in nervous tissues underwent further increases as the illness progressed. Lipid and protein oxidation were observed only at the final stage of the disease after clinical signs had appeared. These findings indicate upregulation of CoQ(9)- and CoQ(10)-dependent antioxidant systems in response to the increased oxidative stress induced by prion infection in nervous tissue. However, the induction of these endogenous antioxidant systems seems to be insufficient to prevent the development of the illness.

Topics: Animals; Antioxidants; Biomarkers; Brain; Cattle; Coenzymes; Disease Models, Animal; Encephalopathy, Bovine Spongiform; Lipid Metabolism; Mice; Mice, Transgenic; Oxidation-Reduction; Oxidative Stress; Prions; PrPSc Proteins; Ubiquinone; Up-Regulation

N-acetylcysteine, beta-glucan, and coenzyme Q10 have been shown to have antioxidant and anti-inflammatory effects on reperfusion injury. The aim of our study was to determine and evaluate the effects of these agents on myocardial ischemia-reperfusion injury.. Forty-four New Zealand white rabbits, all female, weighing 2.4 to 4.1 kg (mean, 3.6 kg) were used in the study. Four study groups of 11 animals were arranged by randomization. The groups were the control group (group C), a group premedicated with coenzyme Q10 (group Q), a group premedicated with beta-glucan (group betaT), and a group premedicated with N-acetylcysteine (group N). After exploration of the heart, a basal myocardial biopsy was taken from the anteroapical left ventricle, and the first blood sampling was done before ischemia. For the ischemia-reperfusion experiments, the major left anterior descending artery was occluded after baseline measurements. After a 45-minute transient ischemic period, the heart was perfused for 120 minutes. After perfusion, the second myocardial biopsy was taken from the anteroapical left ventricle, and the second blood sampling was done. Blood and tissue analysis were performed and evaluated statistically.. Baseline and reperfusion levels of glutathione peroxidase, superoxide dismutase, malonyldialdehyde, and nitric oxide changed significantly. While malonyldialdehyde levels increased in group C, they decreased in the other study groups (P =.001). The increases in glutathione peroxidase and superoxide dismutase levels were significant in all groups except group C (P =.0001 and P <.05, respectively). Levels of nitric oxide were found to be decreased in group C, whereas they increased in the other groups (P =.001).. Antioxidant medication may help in lowering the risk of myocardial ischemia-reperfusion injury. All the medications in our study are shown to have effective roles in preventing ischemia-reperfusion injury to some extent through their antioxidant properties.

Topics: Acetylcysteine; Animals; Antioxidants; beta-Glucans; Coenzymes; Disease Models, Animal; Female; Myocardial Reperfusion Injury; Rabbits; Ubiquinone

In present research the action of coenzyme Q10 on energetic metabolism and antioxidant system at different temperature conditions has been studied. It was established that the addition of coenzyme Q10 caused inadequate stimulation of main metabolic systems that could lead to running out of functional reserves of cardiomyocytes. The use of coenzyme Q10 helped to optimize intracellular compensating mechanisms supplying the defense of myocardium. Introduction in a diet coenzyme Q10 in conditions of a temperature's comfort threshold excess and development of a histic hypoxia can promote the decrease of gravity of hypoxic myocardium's lesions and to glycogenolysis' amplification that promotes maintenance of an energy homeostasis of a myocardium in posthypoxia term. It is possible to assume, that the augmentation of duration of reception coenzyme Q10 or its dosages can render more expressed protective effect.

Topics: Adaptation, Physiological; Animals; Coenzymes; Dietary Supplements; Disease Models, Animal; Energy Metabolism; Housing, Animal; Hypoxia; Male; Myocardium; Rats; Temperature; Ubiquinone

In this study, we aimed to compare the efficacy of methylprednisolone, coenzyme Q(10) and combined methylprednisolone and coenzyme Q(10) treatments on experimental spinal cord injury.. Thirty-two male Sprague-Dawley rats (200-250 g) were divided into four groups. Spinal cord injury (SCI) was performed by placement of an aneurysm clip, extradurally at the level of T4-5. After the trauma, group K (control group) received soybean oil, group M (methylprednisolone group) received 30 mg.kg-1 methylprednisolone and 5.4 mg.kg.hour-1 maintenance dose of methylprednisolone, group Q (coenzyme Q(10) group) received 10 mg.kg-1 coenzyme Q(10), group MQ (methylprednisolone and coenzyme Q(10) group) received 30 mg.kg-1 methylprednisolone and 5.4 mg.kg.hour-1 maintenance dose of methylprednisolone and 10 mg.kg-1 coenzyme Q(10) intraperitoneally. Twenty-four hours after the trauma spinal cord samples of the rats were obtained and tissue samples had been harvested for both biochemical and histopathological evaluation.. In histopathological examination, the edema pattern was significantly more severe in group K than the group M, group Q and group MQ (p<0.001). There was no statistically significant difference between group M, group Q and group MQ regarding edema and bleeding (p>0.05). Mean superoxide dismutase (SOD) scores were significantly low while comparing the group K with all remaining groups and the group MQ comparing with the group M (p<0.05). Mean malondialdehyde (MDA) scores were low in the group M, Q and MQ in comparison with the group K, but there was no statistically significant difference between all groups (p>0.05).. Methylprednisolone, coenzyme Q(10) and combined methylprednisolone and coenzyme Q(10) treatments were found to be effective as they decrease the edema and coenzyme Q(10) could be effective for prevention of secondary injury at experimental SCI.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Therapy, Combination; Edema; Injections, Intraperitoneal; Injury Severity Score; Male; Methylprednisolone; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Superoxide Dismutase; Thoracic Vertebrae; Ubiquinone

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) have been proven to reduce effectively cholesterol level and morbidity and mortality in patients with coronary heart disease and/or dyslipoproteinemia. Statins inhibit synthesis of mevalonate, a precursor of both cholesterol and coenzyme Q (CoQ). Inhibited biosynthesis of CoQ may be involved in some undesirable actions of statins. We investigated the effect of simvastatin on tissue CoQ concentrations in the rat model of NO-deficient hypertension induced by chronic L-NAME administration. Male Wistar rats were treated daily for 6 weeks with L-NAME (40 mg/kg) or with simvastatin (10 mg/kg), another group received simultaneously L-NAME and simvastatin in the same doses. Coenzyme Q(9) and Q(10) concentrations were analyzed by high performance liquid chromatography. L-NAME and simvastatin alone had no effect on CoQ concentrations. However, simultaneous application of L-NAME and simvastatin significantly decreased concentrations of both CoQ homologues in the left ventricle and slightly decreased CoQ(9) concentration in the skeletal muscle. No effect was observed on CoQ level in the liver and brain. We conclude that the administration of simvastatin under the condition of NO-deficiency reduced the level of CoQ in the heart and skeletal muscle what may participate in adverse effect of statins under certain clinical conditions.

Topics: Animals; Brain; Coenzymes; Disease Models, Animal; Down-Regulation; Heart Ventricles; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Liver; Male; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Simvastatin; Time Factors; Ubiquinone

In the current study our objective was to develop a murine model of human hyper-IgD syndrome (HIDS) and severe mevalonic aciduria (MA), autoinflammatory disorders associated with mevalonate kinase deficiency (MKD). Deletion of one Mvk allele (Mvk (+/-)) yielded viable mice with significantly reduced liver Mvk enzyme activity; multiple matings failed to produce Mvk (-/-) mice. Cholesterol levels in tissues and blood, and isoprene end-products (ubiquinone, dolichol) in tissues were normal in Mvk (+/-) mice; conversely, mevalonate concentrations were increased in spleen, heart, and kidney yet normal in brain and liver. While the trend was for higher IgA levels in Mvk (+/-) sera, IgD levels were significantly increased (9-12-fold) in comparison to Mvk (+/+) littermates, in both young (<15 weeks) and older (>15 weeks) mice. Mvk (+/-) animals manifested increased serum TNF-alpha as compared to wild-type littermates, but due to wide variation in levels between individual Mvk (+/-) mice the difference in means was not statistically significant. Mvk (+/-) mice represent the first animal model of HIDS, and should prove useful for examining pathophysiology associated with this disorder.

Topics: Alleles; Animals; Disease Models, Animal; Dolichols; Gene Deletion; Gene Frequency; Humans; Immunoglobulin D; Mevalonate Kinase Deficiency; Mice; Mice, Transgenic; Models, Biological; Models, Genetic; Phosphotransferases (Alcohol Group Acceptor); Ubiquinone

Decylubiquinone treatment in vitro has demonstrated a potent inhibitor effect on reactive oxidative species production. However, the effectin vivo has not been demonstrated yet. Thus, rats SHRSP male were divided in two groups: treated and controls (n=6, each). The treated group received 10 mg/Kg(-)/body weight of decylubiquinone diluted in coconut oil by oral gavage during four weeks. Control rats just received the vehicle. Body weight, diuresis, food and water intake, systolic blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, blood glucose levels and malondialdehyde were determined. There were a significant (p<0.05) reduction on systolic blood pressure, plasma malondialdehyde, total cholesterol and LDL-cholesterol in the treated group. Additionally, HDL-cholesterol also increased significantly. However, body weight, diuresis, food and water intake, blood glucose levels and triglycerides did not alter after treatment. Thus, decylubiquinone can be a new antihypertensive, hypolipidemic and antioxidant agent on the prevention and treatment of diseases linked to oxidative stress.

Topics: Animals; Antihypertensive Agents; Antioxidants; Blood Glucose; Blood Pressure; Disease Models, Animal; Hypolipidemic Agents; Lipids; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Inbred SHR; Ubiquinone

The neuropathological and clinical symptoms of Huntington's disease (HD) can be simulated in animal model with systemic administration of 3-nitropropionic acid (3-NP). Energy defects in HD could be ameliorated by administration of coenzyme Q(10) (CoQ(10)), creatine, or nicotinamid. We studied the activity of creatine kinase (CK) and the function of mitochondrial respiratory chain in the brain of aged rats administered with 3-NP with and without previous application of antioxidants CoQ(10)+vitamin E. We used dynamic and steady-state methods of in vivo phosphorus magnetic resonance spectroscopy ((31)P MRS) for determination of the pseudo-first order rate constant (k(for)) of the forward CK reaction, the phosphocreatine (PCr) to adenosinetriphosphate (ATP) ratio, intracellular pH(i) and Mg(i)(2+) content in the brain. The respiratory chain function of isolated mitochondria was assessed polarographically; the concentration of CoQ(10) and alpha-tocopherol by HPLC. We found significant elevation of k(for) in brains of 3-NP rats, reflecting increased rate of CK reaction in cytosol. The function of respiratory chain in the presence of succinate was severely diminished. The activity of cytochromeoxidase and mitochondrial concentration of CoQ(10) was unaltered; tissue content of CoQ(10) was decreased in 3-NP rats. Antioxidants CoQ(10)+vitamin E prevented increase of k(for) and the decrease of CoQ(10) content in brain tissue, but were ineffective to prevent the decline of respiratory chain function. We suppose that increased activity of CK system could be compensatory to decreased mitochondrial ATP production, and CoQ(10)+vitamin E could prevent the increase of k(for) after 3-NP treatment likely by activity of CoQ(10) outside the mitochondria. Results of our experiments contributed to elucidation of mechanism of beneficial effect of CoQ(10) administration in HD and showed that the rate constant of CK is a sensitive indicator of brain energy disorder reflecting therapeutic effect of drugs that could be used as a new in vivo biomarker of neurodegenerative diseases.

Topics: Adenosine Triphosphate; Animals; Brain; Coenzymes; Creatine Kinase; Disease Models, Animal; Electron Transport Complex IV; Energy Metabolism; Huntington Disease; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Oxidative Phosphorylation; Phosphocreatine; Rats; Rats, Wistar; Ubiquinone; Vitamin E

Huntington's disease (HD) is a fatal neurodegenerative disorder of genetic origin with no known therapeutic intervention that can slow or halt disease progression. Transgenic murine models of HD have significantly improved the ability to assess potential therapeutic strategies. The R6/2 murine model of HD, which recapitulates many aspects of human HD, has been used extensively in pre-clinical HD therapeutic treatment trials. Of several potential therapeutic candidates, both minocycline and coenzyme Q10 (CoQ10) have been demonstrated to provide significant improvement in the R6/2 mouse. Given the specific cellular targets of each compound, and the broad array of abnormalities thought to underlie HD, we sought to assess the effects of combined minocycline and CoQ10 treatment in the R6/2 mouse. Combined minocycline and CoQ10 therapy provided an enhanced beneficial effect, ameliorating behavioral and neuropathological alterations in the R6/2 mouse. Minocycline and CoQ10 treatment significantly extended survival and improved rotarod performance to a greater degree than either minocycline or CoQ10 alone. In addition, combined minocycline and CoQ10 treatment attenuated gross brain atrophy, striatal neuron atrophy, and huntingtin aggregation in the R6/2 mice relative to individual treatment. These data suggest that combined minocycline and CoQ10 treatment may offer therapeutic benefit to patients suffering from HD.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Body Weight; Coenzymes; Cytoprotection; Disease Models, Animal; Drug Therapy, Combination; Humans; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Microglia; Minocycline; Nerve Tissue Proteins; Nuclear Proteins; Survival Rate; Ubiquinone

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10 slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10 from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10 significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10 resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10 and CoQ9 were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10 elevated CoQ10 plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10 exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10 in HD patients are warranted.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenosine Triphosphate; Animals; Body Weight; Coenzymes; Deoxyguanosine; Disease Models, Animal; Dose-Response Relationship, Drug; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Neostriatum; Nerve Tissue Proteins; Neuroprotective Agents; Nuclear Proteins; Rotarod Performance Test; Treatment Outcome; Ubiquinone

Regional distribution of coenzyme Q10 and mitochondrial complex-1 activity were estimated in the brains of control-(C57BL/6), metallothionein knock out-, metallothionein transgenic-, and homozygous weaver mutant mice; and human dopaminergic (SK-N-SH) cells with a primary objective to determine the neuroprotective potential of coenzyme Q10 in Parkinson's disease. Complex-1 activity as well as coenzyme Q10 were significantly higher in the cerebral cortex as compared to the striatum in all the genotypes examined. Complex-1 activity and coenzyme Q10 were significantly reduced in weaver mutant mice and metallothionein knock out mice, but were significantly increased in metallothionein transgenic mice. The reduced complex-1 activity and 18F-DOPA uptake occurred concomitantly with negligible differences in the coenzyme Q10 between in the cerebral cortex and striatum of weaver mutant mice. Administration of coenzyme Q10 increased complex-1 activity and partially improved motoric performance in weaver mutant mice. Direct exposure of rotenone also reduced coenzyme Q10, complex-1 activity, and mitochondrial membrane potential in SK-N-SH cells. Rotenone-induced down-regulation of complex-1 activity was attenuated by coenzyme Q10 treatment, suggesting that complex-1 may be down regulated due to depletion of coenzyme Q10 in the brain. Therefore, metallothionein-induced coenzyme Q10 synthesis may provide neuroprotection by augmenting mitochondrial complex-1 activity in Parkinson's disease.

Topics: Analysis of Variance; Animals; Brain; Cell Line, Tumor; Chromatography, High Pressure Liquid; Coenzymes; Dihydroxyphenylalanine; Disease Models, Animal; Electron Transport Complex I; Fluorine Radioisotopes; Humans; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Mice, Transgenic; Neuroblastoma; Neuroprotective Agents; Parkinson Disease; Positron-Emission Tomography; Statistics as Topic; Tissue Distribution; Ubiquinone

During the period of aging of spontaneously hypertensive rats (SHR) between 6 and 13 weeks the systolic arterial pressure increased from 131+/-2 up to 176+/-3 mm Hg while in the control group of WKY rats it reached 122+/-2 mmHg. The hypertension was combined with myocardial hypertrophy -- the relative weight of SHR heart was 24% higher. The contractile myocardial function of the isolated isovolumic heart of SHR group did not differ from WKY group in a wide range of coronary perfusion rates. During oxidative stress induced by 40-min intracoronary introduction of H(2)O(2) function of hypertrophied SHR hearts fell significantly deeper. This coincided with decreased myocardial activity of superoxide dismutase and glutathione peroxidase by 29-30%, and increased catalase activity by 18%. The rate of generation of active forms of oxygen (hydroxyl radicals HO(.-)) in mitochondria from SHR hearts was higher as compared with WKY. Thus, the development of hypertension was combined with decreased antioxidant protection of the myocardium. The addition of ubiquinone to drinking water (approximately 10 mg/kg/day) for 6 weeks did not affect arterial pressure level, but was associated with two times lesser degree of myocardial hypertrophy. The hearts of SHR that received ubiquinone differed from those not treated with ubiquinone by increased maximal level of myocardial contractile function, and by improved myocardial relaxability and distensibility. After administration of H(2)O(2), myocardial function of SHR was kept on higher level. That was combined with less myocardial oedema, better preservation of antioxidant enzymes and reduced rate of succinate-dependent generation of superoxide radicals in mitochondria from hearts of ubiquinone treated SHR. The results have shown, that administration of ubiquinone to rats with hereditary hypertension reduces degree of myocardial hypertrophy, improves functional properties of the myocardium, promotes effective protection of antioxidant enzymes and increases the resistance of the cardiac muscle to oxidative stress.

Topics: Animals; Blood Pressure; Catalase; Disease Models, Animal; Follow-Up Studies; Glutathione Peroxidase; Hypertension; Myocardial Contraction; Myocardium; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxide Dismutase; Ubiquinone

Untreated or poorly controlled arterial hypertension induced development of pathologic left ventricular hypertrophy (LVH), a common finding in hypertensive patients and a strong predictor of cardiovascular morbidity and mortality. The proteomic approach is a powerful technique to analyze a complex mixture of proteins in various settings. An experimental model of hypertension-induced early LVH was performed in spontaneously hypertensive rats, and the cardiac protein pattern compared with the normotensive Wistar Kyoto counterpart was analyzed. Fifteen altered protein spots were shown in the early stage of LVH. Compared with a previous animal model of established and regressed LVH, three protein spots were common in both models. These three altered protein spots corresponded to two unique proteins that were identified as Calsarcin-1 (CS-1) and ubiquinone biosynthesis protein COQ7 homolog. CS-1 is a negative regulator of the calcineurin/NF-AT pathway. Because upregulation in the expression levels of this protein was observed, the activation level of NF-kappaB by oxidative stress as an alternative pathway was investigated. It was found that antihypertensive therapies partially decreased oxidative stress and normalized the activation of NF-kappaB in the kidneys and aorta NF-kappaB activation but just moderately in the heart. This could be due to the interaction of any specific cardiac protein with any component of the NF-kappaB pathway. In this sense, CS-1 could be a good candidate because it is expressed preferentially in heart, to a lesser extent in smooth muscle cells, but not in kidney. Further investigations are necessary to elucidate the exact role of CS-1 and ubiquinone biosynthesis protein COQ7 in the setting of hypertension-induced LVH.

Topics: Animals; Antihypertensive Agents; Aorta; Carrier Proteins; Disease Models, Animal; Gene Expression Profiling; Hypertension; Hypertrophy, Left Ventricular; Kidney; Male; Microfilament Proteins; Muscle Proteins; Myocardium; NF-kappa B; Oxidative Stress; Proteomics; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Ubiquinone

Mechanisms underlying dilated cardiomyopathy (DCM) are poorly understood and effective therapy is still unavailable. The aim of this study was to examine the heart ultrastructure and dynamic of BIO T0-2 cardiomyopathic hamsters, an animal model of DCM, and to study in these animals, the effects of a co-formulation (HS12607) of propionyl-L-carnitine, coenzyme Q(10) and omega-3 fatty acids on cardiac mechanical parameters. Sarcomere length, Frank-Starling mechanism and force-frequency relations were studied on isolated ventricular papillary muscle from age-matched BIO F1B normal Syrian hamsters, BIO T0-2 control and BIO T0-2 HS12607-treated cardiomyopathic Syrian hamsters. At the optimum length to maximum active force, electron microscopy of left ventricular papillary muscle revealed that seven out of ten muscles studied showed shorter sarcomeres (1.20 +/- 0.29 microm), and the remaining three showed longer sarcomeres (2.80 +/- 0.13 microm), compared to those of normal hamsters (2.05 +/- 0.06 microm, n = 10). Severe alterations of the Frank-Starling mechanism, force-frequency relations and derivative parameters of contractile waves were also observed in vitro in the BIO T0-2 control hamsters. Long-term (8 weeks) treatment with HS12607 prevented alterations in sarcomere length in the BIO T0-2 cardiomyopathic hamsters; the Frank-Starling mechanism and force-frequency relations were also significantly (P < 0.05) improved in these hamsters. Therefore results of the present study strongly suggest the need for clinical studies on metabolic therapeutic intervention in the effort to stop the progression of dilated cardiomyopathy.

Topics: Animals; Cardiomyopathy, Dilated; Carnitine; Cricetinae; Disease Models, Animal; Electric Stimulation; Fatty Acids, Omega-3; Male; Mesocricetus; Myocardial Contraction; Papillary Muscles; Sarcomeres; Ubiquinone

Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associated with cardiomyopathy, is caused by severely reduced frataxin, a mitochondrial protein involved in Fe-S cluster assembly. We have recently generated mouse models that reproduce important progressive pathological and biochemical features of the human disease. Our frataxin-deficient mouse models initially demonstrate time-dependent intramitochondrial iron accumulation, which occurs after onset of the pathology and after inactivation of the Fe-S dependent enzymes. Here, we report a more detailed pathophysiological characterization of our mouse model with isolated cardiac disease by echocardiographic, biochemical and histological studies and its use for placebo-controlled therapeutic trial with Idebenone. The Fe-S enzyme deficiency occurs at 4 weeks of age, prior to cardiac dilatation and concomitant development of left ventricular hypertrophy, while the mitochondrial iron accumulation occurs at a terminal stage. From 7 weeks onward, Fe-S enzyme activities are strongly decreased and are associated with lower levels of oxidative stress markers, as a consequence of reduced respiratory chain activity. Furthermore, we demonstrate that the antioxidant Idebenone delays the cardiac disease onset, progression and death of frataxin deficient animals by 1 week, but does not correct the Fe-S enzyme deficiency. Our results support the view that frataxin is a necessary, albeit non-essential, component of the Fe-S cluster biogenesis, and indicate that Idebenone acts downstream of the primary Fe-S enzyme deficit. Furthermore, our results demonstrate that Idebenone is cardioprotective even in the context of a complete lack of frataxin, which further supports its utilization for the treatment of FRDA.

Topics: Animals; Benzoquinones; Cardiomyopathy, Dilated; Disease Models, Animal; Electrocardiography; Frataxin; Friedreich Ataxia; Iron-Binding Proteins; Iron-Sulfur Proteins; Mice; Mitochondria; Myocardium; Oxidative Stress; Ubiquinone

Because reactive oxygen species have been implicated as mediators of inflammatory bowel disease (IBD), we evaluated the potential preventive and therapeutic effects of two dietary antioxidants, glutathione (GSH) and coenzyme Q10 (CoQ10) on dextran sulfate sodium (DSS)-induced colitis in mice. Fifty female 8-wk old Swiss-Webster mice were randomly assigned to 4 groups for a pre-treatment "prevention" study: (1) GSH (1% of diet); (2) CoQ10 (200 mg/kg/d); (3) DSS only (3% of drinking water); (4) control (no treatment). The mice in groups 1 and 2 were fed with GSH or CoQ10 for 21 wks, and the mice in groups 1, 2 and 3 were provided DSS from wk 7 for 4 cycles (1 cycle = 1 wk DSS followed by 2-wk water). Another 50 mice were randomly assigned to 4 groups for a 21-wk "treatment" study where the mice in groups 1, 2, and 3 were administered DSS for 6 cycles (18 wks) to induce colitis. GSH and CoQ10 were added from wk 7 until the completion of the protocol. Loose stools and hemocult positivity were modestly but significantly reduced with GSH or CoQ10 at several periods during the intervention in both the prevention and treatment studies. In contrast, histological evaluation revealed increases in colonic dysplasia and ulceration with GSH or CoQ10. Thus, in this mouse model, GSH and CoQ10 appear to have a beneficial effect on acute signs of IBD, but may have an adverse impact on the chronic pathophysiology of the disease. Further studies using additional animal models are required to determine whether GSH or CoQ10 provide a favorable or unfavorable benefit:risk ratio in the prevention or treatment of IBD.

Topics: Analysis of Variance; Animals; Antioxidants; Body Weight; Colitis, Ulcerative; Colon; Dextran Sulfate; Diet; Disease Models, Animal; Female; Glutathione; Inflammatory Bowel Diseases; Mice; Random Allocation; Time Factors; Ubiquinone

The HD-N171-82Q (line 81) mouse model of Huntington's disease (HD), expresses an N-terminal fragment of mutant huntingtin (htt), loses motor function, displays HD-related pathological features, and dies prematurely. In the present study, we compare the efficacy with which environmental, pharmacological, and genetic interventions ameliorate these abnormalities. As previously reported for the R6/2 mouse model of HD, housing mice in enriched environments improved the motor skills of N171-82Q mice. However, life expectancy was not prolonged. Significant improvements in motor function, without prolonging survival, were also observed in N171-82Q mice treated with Coenzyme Q10 (CoQ10, an energy metabolism enhancer). Several compounds were not effective in either improving motor skills or prolonging life, including Remacemide (a glutamate antagonist), Celecoxib (a COX-2 inhibitor), and Chlorpromazine (a prion inhibitor); Celecoxib dramatically shortened life expectancy. We also tested whether raising cellular antioxidant capacity by co-expressing high levels of wild-type human Cu/Zn superoxide dismutase 1 (SOD1) was beneficial. However, no improvement in motor performance or life expectancy was observed. Although we would argue that positive outcomes in mice carry far greater weight than negative outcomes, we suggest that caution may be warranted in testing Celecoxib in HD patients. The positive outcomes achieved by CoQ10 therapy and environmental stimuli point toward two potentially therapeutic approaches that should be readily accessible to HD patients and at-risk family members.

Topics: Acetamides; Animals; Celecoxib; Chlorpromazine; Coenzymes; Cyclooxygenase Inhibitors; Disease Models, Animal; Disease Progression; Dopamine Antagonists; Environment, Controlled; Female; Humans; Huntington Disease; Mice; Mice, Transgenic; Motor Activity; Motor Skills; Neuroprotective Agents; Phenotype; Pyrazoles; Sulfonamides; Superoxide Dismutase; Superoxide Dismutase-1; Survival Rate; Treatment Outcome; Ubiquinone

Skeletal muscle wasting is a prominent feature of cancer cachexia and involves decreased muscle protein synthesis and increased activity of the ubiquitin-proteasome pathway of protein degradation. We report that both indomethacin and ibuprofen improved body weight and weight of the gastrocnemius muscle in tumor-bearing mice. Ibuprofen increased the soluble protein content of the muscle without affecting muscle levels of phosphorylated p70 S6 kinase, a ribosomal kinase involved in protein synthesis. Paradoxically, indomethacin increased levels of ubiquitin-conjugated proteins. Further study is needed to understand the mechanism of action by which indomethacin and ibuprofen preserve body weight and muscle mass in the tumor-bearing mice. The data suggest that ibuprofen may have beneficial effects in the treatment of cancer cachexia.

Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cachexia; Colonic Neoplasms; Disease Models, Animal; Female; Ibuprofen; Indomethacin; Mice; Muscle, Skeletal; Neoplasms, Experimental; Ubiquinone

The effects of exogenous toxins (MPP(+), rotenone) and potentially neurotoxic properties of levodopa (L-DOPA) on the survival rate of dopaminergic neurons in dissociated primary culture are presented. Dopamine agonists show a capacity to counteract MPP(+)-toxicity. Moreover, a preserving potential of the antioxidant and bioenergetic coenzyme Q(10) (CoQ(10)) on the activities of tyrosine hydroxylase (TH), complexes I and II of the respiratory chain, and hexokinase activity in striatal slice cultures against MPP(+) is demonstrated.

Topics: Animals; Coenzymes; Disease Models, Animal; Dopamine; Dopamine Agonists; Mice; Mice, Inbred C57BL; Neurons; Neurotoxins; Oxidative Stress; Parkinson Disease; Tyrosine 3-Monooxygenase; Ubiquinone

Coenzyme Q10 (CoQ10, ubiquinone) is a highly mobile electron carrier in the mitochondrial respiratory chain that also acts as an antioxidant. We evaluated the neuroprotective efficacy of CoQ10 against fatality in an experimental model of endotoxemia that mimics systemic inflammatory response syndrome using a novel water-soluble formulation of this quinone derivative. Experiments were conducted in adult male Sprague-Dawley rats that were maintained under propofol anesthesia. Intravenous administration of Escherichia coli lipopolysaccharide (LPS; 30 mg/kg) induced progressive hypotension, with death ensuing within 4 h. The sequence of cardiovascular events during this LPS-induced endotoxemia can be divided into a reduction (Phase I), followed by an augmentation (Phase II; "pro-life" phase) and a secondary decrease (Phase III; "pro-death" phase) in the power density of the vasomotor components (0-0.8 Hz) of systemic arterial pressure signals. Pretreatment by microinjection bilaterally of CoQ10 (1 or 2 microg) into the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic vasomotor tone, significantly diminished mortality, prolonged survival time, and reduced the slope or magnitude of the LPS-induced hypotension. CoQ10 pretreatment also significantly prolonged the duration of and augmented the total power density of the vasomotor components of systemic arterial pressure signals in Phase II endotoxemia. The increase in superoxide anion production induced by LPS at the RVLM during Phases II and III endotoxemia was also significantly blunted. We conclude that CoQ10 provides neuroprotection against fatality during experimental endotoxemia by reducing superoxide anion production at the RVLM, whose neuronal activity is intimately related to the "life-and-death" process.

Topics: Animals; Coenzymes; Disease Models, Animal; Endotoxemia; Escherichia coli; Lipopolysaccharides; Male; Medulla Oblongata; Microinjections; Rats; Rats, Sprague-Dawley; Superoxides; Survival Rate; Time Factors; Ubiquinone

Parkinson's disease is characterized by dopamine cell loss of the substantia nigra. Parkinson's disease and the neurotoxin 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine may destroy dopamine neurons through oxidative stress. Coenzyme Q is a cofactor of mitochondrial uncoupling proteins that enhances state-4 respiration and eliminate superoxides. Here we report that short-term oral administration of coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine administration in monkeys.

Topics: Animals; Cell Count; Cell Respiration; Chlorocebus aethiops; Disease Models, Animal; Dopamine; Gene Expression; Ion Channels; Male; Membrane Transport Proteins; Mitochondria; Mitochondrial Proteins; Parkinsonian Disorders; Proteins; RNA, Messenger; Substantia Nigra; Ubiquinone; Uncoupling Agents; Uncoupling Protein 2

Increasing evidence shows that the overproduction of reactive oxygen species, induced by diabetic hyperglycemia, contributes to the development of several cardiopathologies. The susceptibility of diabetic hearts to oxidative stress, induced in vitro by ADP-Fe2+ in mitochondria, was studied in 12-month-old Goto-Kakizaki rats, a model of non-insulin dependent diabetes mellitus, and normal (non-diabetic) Wistar rats. In terms of lipid peroxidation the oxidative damage was evaluated on heart mitochondria by measuring both the O2 consumption and the concentrations of thiobarbituric acid reactive substances. Diabetic rats display a more intense formation of thiobarbituric acid reactive substances and a higher O2 consumption than non-diabetic rats. The oxidative damage, assessed by electron microscopy, was followed by an extensive effect on the volume of diabetic heart mitochondria, as compared with control heart mitochondria. An increase in the susceptibility of diabetic heart mitochondria to oxidative stress can be explained by reduced levels of endogenous antioxidants, so we proceeded in determining alpha-tocopherol, GSH and coenzyme Q content. Although no difference of alpha-tocopherol levels was found in diabetic rats as compared with control rat mitochondria, a significant reduction in GSH (21.5% reduction in diabetic rats) and coenzyme Q levels of diabetic rats was observed. The data suggest that a significant decrease of coenzyme Q9, a potent antioxidant involved in the elimination of mitochondria-generated reactive oxygen species, may be responsible for an increased susceptibility of diabetic heart mitochondria to oxidative damage.

Topics: Animals; Antioxidants; Diabetes Mellitus, Type 2; Disease Models, Animal; Glutathione; In Vitro Techniques; Lipid Peroxidation; Male; Microscopy, Electron; Mitochondria, Heart; Oxidative Stress; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Ubiquinone

Diabetes, which causes enhanced oxidative stress, is a multifactorial disease that leads to deleterious effects in many organ systems within the body. Ubiquinones (coenzyme Q(9) and Q(10)) are amphipathic molecular components of the electron transport chain that function also as endogenous antioxidants and attenuate the diabetes-induced decreases in antioxidant defense mechanisms. Insulin-like growth factor 1 (IGF-1) is considered to be an "essential surviving factor", the level and function of which are compromised in diabetes. This study investigated the impact of IGF-1 supplementation on ubiquinone levels in a rat model of type I diabetes. Adult male Sprague-Dawley rats were divided into four groups: control, control plus IGF-1, diabetic and diabetic plus IGF-1. Diabetic animals received a single intravenous injection of streptozotocin (STZ, 55 mg/kg). IGF-1 supplementation groups received a daily intraperitoneal dose of 3 mg IGF-1 per kilogram body weight for 7 weeks. Coenzyme Q(9) and Q(10) levels were assessed by ultraviolet detection on high pressure liquid chromatography. STZ caused a significant reduction in body weight and an elevation in blood glucose level, which were not prevented by IGF-1 supplementation. In addition Q(9) and Q(10) levels in diabetic liver were significantly elevated. IGF-1 supplementation prevented liver alterations in Q(10) but not Q(9) levels. Q(9) and Q(10) levels in diabetic kidney were significantly depressed, and these deleterious effects were abolished by IGF-1 treatment. These data suggest that IGF-1 antagonizes the diabetes-induced alterations in endogenous antioxidants including coenzyme Q(10), and hence may have a therapeutic role in diabetes.

Topics: Animals; Coenzymes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dietary Supplements; Disease Models, Animal; Insulin-Like Growth Factor I; Kidney; Liver; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reference Values; Ubiquinone

Oxygen/nitrogen reactive species (ROS/RNS) are currently implicated in the pathogenesis of ulcerative colitis, drawing attention on the potential prophylactic and healing properties of antioxidants, scavengers, chelators. We evaluated the possible protective/curative effects of a natural antioxidant preparation based on Aloe vera and ubiquinol, against intestinal inflammation, lesions, and pathological alterations of the intestinal electrophysiological activity and motility, in a rat model of DSS-induced colitis. 5% dextrane sulfate (DDS) (3 days), followed by 1% DSS (4 days) was administered in drinking water. The antioxidant formulation (25 mg/kg) was delivered with a pre-treatment protocol, or simultaneously or post-colitis induction. Spontaneous and acetylcholine-stimulated electrical activity were impaired in the small intestine and in distal colon, upon exposure to DSS only. Severe inflammation occurred, with increased myeloperoxidase activity, and significant alterations of the oxidant/antioxidant status in colonic tissue and peritoneal cells. Lipoperoxidation, superoxide production, glutathione peroxidase and glutathione-S-transferase activities, and reduced glutathione content increased, whilst superoxide dismutase and catalase activities were sharply suppressed in colon tissue. ROS/RNS formation in peritoneal cells was strongly inhibited. Inflammation, electrical/mechanical impairment in the gut, and a great majority of oxidative stress parameters were improved substantially by pre-treatment with the antioxidant preparation, but not by simultaneous administration or post-treatment.

Topics: Acetylcholine; Aloe; Animals; Antioxidants; Catalase; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Electrophysiology; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Intestine, Small; Lipid Peroxidation; Male; Muscle, Smooth; Rats; Rats, Wistar; Reactive Nitrogen Species; Reactive Oxygen Species; Superoxide Dismutase; Superoxides; Ubiquinone

There is substantial evidence that bioenergetic defects and excitotoxicity may play a role in the pathogenesis of Huntington's disease (HD). Potential therapeutic strategies for neurodegenerative diseases in which there is reduced energy metabolism and NMDA-mediated excitotoxicity are the administration of the mitochondrial cofactor coenzyme Q10 and the NMDA antagonist remacemide. We found that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD. The combined treatment, using coenzyme Q10 and remacemide together, was more efficacious than either compound alone, resulting in an approximately 32 and 17% increase in survival in the R6/2 and N171-82Q mice, respectively. Magnetic resonance imaging showed that combined treatment significantly attenuated ventricular enlargement in vivo. These studies further implicate defective energy metabolism and excitotoxicity in the R6/2 and N171-82Q transgenic mouse models of HD and are of interest in comparison with the outcome of a recent clinical trial examining coenzyme Q10 and remacemide in HD patients.

Topics: Acetamides; Administration, Oral; Animals; Behavior, Animal; Body Weight; Brain; Cerebral Ventricles; Coenzymes; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Drug Synergism; Female; Humans; Huntingtin Protein; Huntington Disease; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Motor Activity; Nerve Tissue Proteins; Nuclear Proteins; Organ Size; Survival Rate; Treatment Outcome; Ubiquinone

Oxidative modification of lipoproteins may trigger and maintain atherogenesis. We compared the effects of different antioxidants (alpha-tocopherol, probucol, ubiquinone-10) at doses similar to those used in humans in Watanabe Heritable Hyperlipidemic (WHHL) rabbits for 12 months. Aortic lesions were analyzed for their extent and cellular composition of lesions, mean thickness of fibrous caps and density of smooth muscle cells therein, content of antioxidants, non-oxidized and oxidized lipids. Compared to controls, probucol significantly lowered the extent and macrophage content of lesions and increased the existence and smooth muscle cell density of fibrous caps. alpha-Tocopherol supplementation increased the aortic content of vitamin E, but had no decreasing effect on either the accumulation of macrophage-specific antigen in the aorta or lesion size. Nevertheless, both probucol and alpha-tocopherol significantly decreased in vitro LDL oxidizability, measured under typically strong oxidative conditions. Ubiquinone-10 supplement increased lesion size and the fraction of lesions containing fibrous caps; however, LDL oxidizability remained unaffected by ubiquinone-10 treatment. None of the antioxidants tested lowered oxidized lipids within aortic tissue; however, long-term treatment with probucol provided the most effective anti-atherosclerotic effect, while alpha-tocopherol may be pro-atherogenic and ubiquinone-10 exerts ambivalent effects. Our data suggest that (i) widely used oxidation measures, such as ex-vivo LDL oxidizability, do not reflect the degree of atherosclerosis; and (ii) long-term beneficial effects of relatively low doses of antioxidants may be outweighed by high levels of plasma cholesterol in WHHL rabbits.

Topics: alpha-Tocopherol; Animals; Antioxidants; Aorta; Arteriosclerosis; Coenzymes; Disease Models, Animal; Female; Humans; Lipids; Lipoproteins, LDL; Male; Probucol; Rabbits; Ubiquinone; Vitamin E

Intimal oxidation of LDL is considered an important early event in atherogenesis, and certain antioxidants are antiatherogenic. Dietary coenrichment with vitamin E (VitE) plus ubiquinone-10 (CoQ(10), which is reduced during intestinal uptake to the antioxidant ubiquinol-10, CoQ(10)H(2)) protects, whereas enrichment with VitE alone can increase oxidizability of LDL lipid against ex vivo oxidation. In the present study, we tested whether VitE plus CoQ(10) cosupplementation is more antiatherogenic than either antioxidant alone, by use of apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet without (control) or with 0.2% (wt/wt) VitE, 0.5% CoQ(10), or 0.2% VitE plus 0.5% CoQ(10) (VitE+CoQ(10)) for 24 weeks. None of the supplements affected plasma cholesterol concentrations, whereas in the VitE and CoQ(10) groups, plasma level of the respective supplement increased. Compared with control, plasma from CoQ(10) or VitE+CoQ(10) but not VitE-supplemented animals was more resistant to ex vivo lipid peroxidation induced by peroxyl radicals. VitE supplementation increased VitE levels in aorta, heart, brain, and skeletal muscle, whereas CoQ(10) supplementation increased CoQ(10) only in plasma and aorta and lowered tissue VITE: All treatments significantly lowered aortic cholesterol compared with control, but only VitE+CoQ(10) supplementation significantly decreased tissue lipid hydroperoxides when expressed per parent lipid. In contrast, none of the treatments affected aortic ratios of 7-ketocholesterol to cholesterol. Compared with controls, VitE+CoQ(10) supplementation decreased atherosclerosis at the aortic root and arch and descending thoracic aorta to an extent that increased with increasing distance from the aortic root. CoQ(10) significantly inhibited atherosclerosis at aortic root and arch, whereas VitE decreased disease at aortic root only. Thus, in apoE-/- mice, VitE+CoQ(10) supplements are more antiatherogenic than CoQ(10) or VitE supplements alone and disease inhibition is associated with a decrease in aortic lipid hydroperoxides but not 7-ketocholesterol.

Topics: Animals; Antioxidants; Aorta; Aortic Diseases; Apolipoproteins E; Arteriosclerosis; Cholesterol, VLDL; Coenzymes; Dietary Fats; Disease Models, Animal; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Ubiquinone; Vitamin E

Because several studies indicated that peroxisomes are important for the biosynthesis of isoprenoids, we wanted to investigate whether a reduced availability of isoprenoids could be one of the pathogenic factors contributing to the severe phenotype of the Pex5(-/-) mouse, a model for Zellweger syndrome. Total cholesterol was determined in plasma, brain and liver of newborn mice. In none of these tissues a significant difference was observed between Pex5(-/-) and wild type or heterozygous mice. The hepatic ubiquinone content was found to be even higher in Pex5(-/-) mice as compared to wild type or heterozygous littermates. To investigate whether the Pex5(-/-) fetuses are able to synthesise their own isoprenoids, fibroblasts derived from these mice were incubated with radiolabeled mevalonolactone as a substrate for isoprenoid synthesis. No significant difference was observed between the cholesterol production rates of Pex5(-/-) and normal fibroblasts. Our results show that there is no deficiency of isoprenoids in newborn Pex5(-/-) mice, excluding the possibility that a lack of these compounds is a determinant factor in the development of the disease state before birth.

Topics: Animals; Animals, Newborn; Cholesterol; Disease Models, Animal; Heterozygote; Liver; Mice; Mice, Knockout; Peroxisome-Targeting Signal 1 Receptor; Receptors, Cytoplasmic and Nuclear; Succinate Cytochrome c Oxidoreductase; Terpenes; Ubiquinone; Zellweger Syndrome

Because diabetes mellitus is associated with impairment of testicular function, ultimately leading to reduced fertility, this study was conducted to evaluate the existence of a cause-effect relationship between increased oxidative stress in diabetes and reduced mitochondrial antioxidant capacity. The susceptibility to oxidative stress and antioxidant capacity (in terms of glutathione, coenzyme Q, and vitamin E content) of testis mitochondrial preparations isolated from Goto-Kakizaki (GK) non-insulin-dependent diabetic rats and from Wistar control rats, 1 yr of age, was evaluated. It was found that GK mitochondrial preparations showed a lower susceptibility to lipid peroxidation induced by ADP/Fe(2+), as evaluated by oxygen consumption and reactive oxygen species generation. The decreased susceptibility to oxidative stress in diabetic rats was associated with an increase in mitochondrial glutathione and coenzyme Q9 contents, whereas vitamin E was not changed. These results demonstrate a higher antioxidant capacity in diabetic GK rats. We suggest this is an adaptive response of testis mitochondria to the increased oxidative damage in diabetes mellitus.

Topics: Animals; Antioxidants; Coenzymes; Diabetes Mellitus, Type 2; Disease Models, Animal; Glutathione; Glutathione Disulfide; Male; Mitochondria; Oxidative Stress; Oxygen Consumption; Rats; Rats, Inbred Strains; Rats, Wistar; Reactive Oxygen Species; Testis; Ubiquinone; Vitamin E

Antioxidants in the blood plasma of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. For this initial study an animal model of CCl(4) poisoning was studied. The time (2, 7, and 16 h) and dose (120 and 1200 mg/kg, intraperitoneally)-dependent effects of CCl(4) on plasma levels of alpha-tocopherol, coenzyme Q (CoQ), ascorbic acid, glutathione (GSH and GSSG), uric acid, and total antioxidant capacity were investigated to determine whether the oxidative effects of CCl(4) would result in losses of antioxidants from plasma. Concentrations of alpha-tocopherol and CoQ were decreased in CCl(4)-treated rats. Because of concomitant decreases in cholesterol and triglycerides, it was impossible to dissociate oxidation of alpha-tocopherol and the loss of CoQ from generalized lipid changes, due to liver damage. Ascorbic acid levels were higher with treatment at the earliest time point; the ratio of GSH to GSSG generally declined, and uric acid remained unchanged. Total antioxidant capacity showed no significant change except for 16 h after the high dose, when it was increased. These results suggest that plasma changes caused by liver malfunction and rupture of liver cells together with a decrease in plasma lipids do not permit an unambiguous interpretation of the results and impede detection of any potential changes in the antioxidant status of the plasma.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Carbon Tetrachloride Poisoning; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Free Radicals; Glutathione; Liver; Oxidative Stress; Rats; Rats, Inbred F344; Ubiquinone; Uric Acid; Vitamin E

Expression of immediate early genes has been reported during reperfusion after ischemia in rat livers due to oxygen radical formation. This study investigates in perfused pig livers the effect of the antioxidant idebenone and of cold ischemia time on the gene expression of c-fos and c-jun.. Livers were perfused for 210 min after 0.5 h or 20 h ischemic storage (4 degrees C). One group of pigs was fed idebenone (280 mg/day/7days) prior to organ harvesting. C-fos and c-jun mRNA were determined by RT-PCR at 3, 30, 60, 120 180, 210 min during reperfusion.. Lipid peroxidation increased in liver tissue form 0.54 +/- 0.21 to 1. 09 +/- 0.54 nmol MDA/mg protein during reperfusion after 20 h compared to 0.5 h cold storage. This was antagonized by idebenone (0. 68 +/- 0.20 nmol/MDA/mg protein). C-fos and c-jun were strongly induced in livers stored for 20 h, which was attenuated by idebenone (p < 0.05).. These findings suggest that cold ischemia time and oxygen radicals are critical for immediate early gene expression and that application of an effective antioxidant can attenuate this early stress reaction of the pig liver.

Topics: Animals; Antioxidants; Benzoquinones; Cold Temperature; Disease Models, Animal; Female; Gene Expression Regulation; Genes, fos; Genes, jun; Humans; In Vitro Techniques; Lipid Peroxidation; Liver; Liver Transplantation; Male; Molecular Structure; Perfusion; Rats; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Ubiquinone

Coenzyme Q10 (CoQ10) is essential for ATP generation and has antioxidant properties. Decreased CoQ10 levels have been reported in human heart failure (CHF), but it remains unclear if this is a conserved feature of CHF. The objective of the study was to determine if tachycardia-induced CHF in the dog is associated with reduced CoQ10 levels. Furthermore, it was hypothesized that CoQ10 supplementation may improve CHF severity by preventing CoQ10 deficiency (if present) or via antioxidant effects.. Serum and myocardial levels of CoQ10 were examined in normal dogs (n = 6), dogs with CHF (control, n = 5), and dogs with CHF treated with CoQ10 (CoQ10; 10 mg/kg/day, n = 5). Serum CoQ10 levels did not change with CHF in control dogs, and myocardial levels were similar to those of normal dogs. CoQ10 therapy increased serum but not myocardial levels of CoQ10. In early CHF, CoQ10-treated dogs had lower filling pressures, and, in severe CHF, CoQ10-treated dogs had less hypertrophy as compared with untreated dogs. Other indices of CHF severity were similar in control and CoQ10-treated dogs.. These data indicate that CoQ10 deficiency is not present in this model of CHF. Although dramatic effects on hemodynamics were not observed, CoQ10 supplementation did appear to attenuate the hypertrophic response associated with CHF. Key words: enzymes, cardiomyopathy, hormones, antioxidant.

Topics: Animals; Antioxidants; Coenzymes; Disease Models, Animal; Dogs; Heart Failure; Hypertrophy; Male; Myocardium; Tachycardia; Ubiquinone

The aim of the work was to evaluate an influence of CoQ(10) on lactate acidosis, adenosine-5'-triphosphate (ATP) concentrations, oxidized to reduced glutathione ratio and on superoxide dismutase activity in endothelin model of cerebral ischemia in the rat. Light microscopic studies in the central nervous system and morphometric analysis of pyramidal cells in the hippocampus were also performed. Endothelins (ET-1 or ET-3; 20 pmoles) were injected into the right lateral cerebral ventricle (intracerebroventricularly). CoQ(10) was given intraperitoneally (i.p.) just before the operation (i.p. 10 mgkg b. wt.). More severe changes of investigated biochemical parameters were observed in the animals treated with ET-1 in comparison with ET-3. Recovery was noted earlier in the group subjected to ET-3 and CoQ(10) administration, than in the animals subjected to ET-1 and CoQ(10) treatment. Histopathological observations showed sparse foci of a neuronal loss in the cerebral cortex and in the hippocampus only in the ET-1 model of ischemia. Additionally more numerous dark neurons were present in above brain structures following ET-1 administration comparing with ET-3 one. Morphometrical studies demonstrated that CoQ(10) diminished neuronal injury in the hippocampal CA1, CA2 and CA3 zones. Above data indicate on neuroprotective effect of CoQ(10) as a potent antioxidant and oxygen derived free radicals scavenger in the cerebral ischemia.

Topics: Adenosine Triphosphate; Animals; Brain; Brain Ischemia; Brain Stem; Cerebellum; Cerebral Cortex; Cerebral Ventricles; Coenzymes; Disease Models, Animal; Endothelin-1; Functional Laterality; Glutathione; Glutathione Disulfide; Hippocampus; Injections, Intraventricular; Lactates; Male; Neurons; Pyramidal Cells; Rats; Rats, Wistar; Superoxide Dismutase; Ubiquinone

Cardiomyopathic hamsters develop heart disease early in life, which leads to congestive heart failure and death as these hamsters age. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to reduce ubiquinone concentrations and to deteriorate myocardial function in humans and in experimental animals. HMG-CoA reductase inhibitors differ regarding their ability to penetrate extrahepatic tissues. As a consequence, lovastatin inhibits cholesterol biosynthesis at least 100-fold more effectively than pravastatin in extrahepatic cells. We examined the effect of lovastatin and pravastatin (approximately 10 mg per kilogram of body weight and per day mixed in the diet) compared with controls on the lifespan of cardiomyopathic hamsters (BIO 8262 strain) in the heart-failure period. In male hamsters, neither lovastatin nor pravastatin significantly affected survival. In female hamsters, lovastatin reduced median survival time from 89 days (control animals) to 30 days (P <.05); pravastatin (median survival, 115 days) had no statistically significant effect. We conclude that lovastatin, but not pravastatin, at a daily dose of 10 mg per kilogram of body weight significantly increases the mortality of cardiomyopathic hamsters. This effect may be the result of inhibition of myocardial ubiquinone supply.

Topics: Administration, Oral; Animals; Anticholesteremic Agents; Cardiomyopathies; Cricetinae; Disease Models, Animal; Female; Lovastatin; Male; Pravastatin; Sex Factors; Survival Analysis; Ubiquinone

An animal model of chronic fluorosis was produced by subjecting Wistar rats to high doses of fluoride in drinking water for a prolonged period. Phospholipid and neutral lipid contents in rat kidney were then analyzed by high-performance liquid chromatography (HPLC), and fatty acid compositions from individual phospholipids were measured by gas chromatography. Lipid peroxidation was detected by the thiobarbituric-acid-reactive substance assay. Results showed that the total phospholipid content significantly decreased in the kidney of the rats treated with high doses of fluoride and the main species influenced were phosphatidylethanolamine (PE) and phosphatidylcholine (PC). Decreased proportions of polyunsaturated fatty acids were observed in PE and PC in kidney of fluoride-treated animals compared to controls. No changes could be detected in the amounts of cholesterol and dolichol in kidneys between the rats treated with fluoride and controls. A significant decrease of ubiquinone in rat kidney was observed in the groups treated with excessive fluoride. High levels of lipid peroxidation were detected in kidney of the rats with fluorosis. It is plausible that the specific modification of lipid composition results from lipid peroxidation. The oxidative stress and modification of cellular membrane lipids may be involved in the pathogenesis of chronic fluorosis and provide a possible explanation for the gross system damage observed in the body, especially in soft tissues and organs.

Topics: Animals; Calcium Fluoride; Cholesterol; Chromatography, High Pressure Liquid; Disease Models, Animal; Dolichols; Fatty Acids, Unsaturated; Female; Fluoride Poisoning; Intracellular Membranes; Kidney; Lipid Peroxidation; Male; Membrane Lipids; Phosphatidylcholines; Phosphatidylethanolamines; Rats; Rats, Wistar; Ubiquinone; Water Supply

Ischemia and subsequent reperfusion induce lipid peroxidation in the cerebrum of the fetal rat. The present study evaluated the antioxidant activity of endogenous coenzyme Q in protecting against the lipid peroxidation induced in the fetal rat brain by ischemia/reperfusion.. We used wistar rats at day 19 of pregnancy. Fetal ischemia was induced by bilateral occlusion of the utero-ovarian artery for 20 minutes. For reperfusion, the occlusion was released and the circulation was restored for 30 minutes. Control rats underwent sham operation. We determined the levels of thiobarbituric acid-reactive substances, the concentrations of coenzyme Q9, coenzyme Q10, and the mitochondrial respiratory control index in fetal brains.. Occlusion for 20 minutes significantly reduced the respiratory control index (p < 0.01), but did not alter the levels of thiobarbituric acid-reactive substances, coenzyme Q9 or coenzyme Q10. Subsequent reperfusion, however, significantly increased the level of thiobarbituric acid-reactive substances (from 6.53+/-1.54 to 11.46+/-3.31 nM/mg of protein, p < 0.01) and significantly decreased the level of coenzyme Q9 (from 291.73+/-108.94 to 162.44+/-56.83 pM/mg of protein, p < 0.05) and that of coenzyme Q10 (from 153.10+/-75.24 to 79.84+/-30.40 pM/mg of protein, p < 0.05). The respiratory control index was still significantly lower following reperfusion than in controls (p < 0.01). Significant negative correlations were observed between the level of thiobarbituric acid-reactive substances and the concentrations of either coenzyme Q9 (r = -0.68, p < 0.001) or coenzyme Q10 (r = -0.70, p < 0.001).. Endogenous coenzyme Q may protect the fetal rat brain against the lipid peroxidation induced by ischemia/reperfusion.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Female; Fetal Hypoxia; Lipid Peroxidation; Mitochondria; Oxygen Consumption; Pregnancy; Rats; Rats, Wistar; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Ubiquinone

The aim of the work was to evaluate the influence of CoQ10 on superoxide dismutase (SOD) activity levels in the rat model of cerebral ischemia induced by endothelins (ET-1 or ET-3). ETs (20 pmol) were injected into the right lateral cerebral ventricle and immediately CoQ10 was given intraperitoneally (10 mg/kg b.w.). In the brains of experimental animals subjected both to ET-1 and ET-2 administration there was observed a decrease of SOD activity in the brain stem, in the cerebrallum and in the cerebral cortex at all time intervals. ET-1, as compared to ET-3 evoked longer lasting disturbances in SOD activity. In the cerebellum and in the cerebral cortex positive effect of CoQ10 and recovery to the control values was noted after 4 hours in the group subjected to ET-3 injection and after 24 hours in the ET-1 treated animal. Investigated brain areas showed different sensitivity to ETs. Above data may indicate on beneficial effect CoQ10 in the cerebral ischemia via decrease of free radicals concentration.

Topics: Animals; Brain Ischemia; Brain Stem; Cerebellum; Cerebral Cortex; Coenzymes; Disease Models, Animal; Endothelin-1; Endothelin-3; Male; Rats; Rats, Wistar; Superoxide Dismutase; Ubiquinone

In order to examine whether iron and alcohol act synergistically during tumor initiation in vivo, we investigated the effects of dietary iron overload and a liquid ethanol-containing diet on the initiation phase of the Solt & Farber model of chemical hepatocarcinogenesis.. Following dietary supplementation with carbonyl iron for 8 weeks and ethanol pair-feeding according to Lieber deCarli for 5 weeks, animals were subjected to partial hepatectomy in order to induce regenerative cell proliferation and thereby "fix" putative DNA lesions. Levels of malondialdehyde, reduced and oxidized ubiquinone-9, alpha-tocopherol and 8-oxo-2'-deoxyguanosine were analyzed in liver tissue removed at the time of partial hepatectomy, and blood was collected for determination of alanine amino-transferase activities. Following a 2-week recovery period, promotion was achieved with 0.02% dietary 2-acetylaminofluorene and carbon tetrachloride. Two weeks after the completion of promotion, animals were sacrificed and the number of preneoplastic, glutathione S-transferase 7,7-positive lesions counted. Animals initiated with diethylnitrosamine served as a positive control group.. Serum aminotransferase activities were significantly increased, and hepatic contents of ubiquinol-9 (reduced ubiquinone-9) were significantly decreased in animals exposed to the combination of iron and ethanol in comparison to the other groups. Livers from iron-treated animals had decreased levels of alpha-tocopherol and increased contents of malondialdehyde, whereas treatment with ethanol did not further enhance these alterations. Levels of 8-oxo-2'-deoxyguanosine were not significantly different in animals treated with iron, ethanol or iron + ethanol as compared with controls. The number of preneoplastic foci at the time of sacrifice was not increased in livers exposed to iron and/or ethanol as compared with those from control animals. As expected, the number of foci was significantly increased in positive controls which were initiated with diethylnitrosamine.. Iron potentiated the cytotoxic effects of ethanol, resulting in increased serum aminotransferase activities and decreased hepatic contents of ubiquinol. However, the combination of iron and ethanol did not exert genotoxic effects detectable as enhanced hepatic levels of 8-oxo-2'-deoxyguanosine, or increased formation of preneoplastic, glutathione S-transferase 7,7-positive lesions in the Solt & Farber model of chemical hepatocarcinogenesis.

Topics: Alanine Transaminase; Animals; Antioxidants; Body Weight; Disease Models, Animal; Ethanol; Iron Overload; Liver; Liver Neoplasms, Experimental; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley; Rats, Wistar; Ubiquinone; Vitamin E

Coenzyme Q10 has been found to enhance recovery of function after reperfusion in numerous experimental acute ischemia-reperfusion models. We assessed whether coenzyme Q10, administered intravenously either during or 1 h before ischemia, can limit infarct size in the rabbit.. Anesthetized open-chest rabbits were subjected to 30 min of coronary artery occlusion and 4 h of reperfusion. In Protocol 1, 12 min after beginning of ischemia rabbits were randomized to intravenous infusion of 30 mg coenzyme Q10 (Eisai Co., Japan) (n = 10) or vehicle (n = 10). In Protocol 2, rabbits were randomized to 30 mg coenzyme Q10 (n = 6) or vehicle (n = 6) treatment 60 min before ischemia. Ischemic zone at risk (IZ) was assessed by blue dye and necrotic zone (NZ) by tetrazolium staining.. In both protocols, coenzyme Q10 did not alter heart rate, mean blood pressure, or regional myocardial blood flows in either the ischemic or non-ischemic zones during ischemia or reperfusion. No difference was found in IZ (as fraction of LV weight) (Protocol 1: 0.24 +/- 0.02 vs. 0.25 +/- 0.02; Protocol 2: 0.28 +/- 0.02 vs. 0.28 +/- 0.03, in the control vs. coenzyme Q10 groups, respectively). The NZ/IZ ratio was comparable between the groups in both protocols (Protocol 1: 0.22 +/- 0.04 vs. 0.26 +/- 0.04; Protocol 2: 0.21 +/- 0.06 vs. 0.30 +/- 0.06, in the control vs. coenzyme Q10 groups, respectively).. Coenzyme Q10, administered acutely either during or 60 min before myocardial ischemia, does not attenuate infarct size in the rabbit.

Topics: Animals; Coenzymes; Disease Models, Animal; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Rabbits; Random Allocation; Ubiquinone

The effect of coenzyme Q10 (CoQ10) on hepatocyte injury during endotoxin (ET) shock in rats was studied with special reference to the role of polymorphonuclear neutrophils (PMN). ET shock was induced by intravenous administration of 5 mg/kg ET, and CoQ10 was given at 20 mg/kg once or 3 times orally or intravenously. We examined plasma glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and glutamate dehydrogenase (GLDH) levels, superoxide production by PMN, the phagocytic activity of PMN, the cytotoxicity of PMN to liver cells, and histological changes in the liver. The CoQ10-treated rats showed lower levels of GOT, GPT, and GLDH than rats treated with ET only. When compared to the group given ET only superoxide production by PMN induced by 2-methyl-6-phenyl-3,7-dihydroimidazol [1,2-alpha]pyrazin-3-one (MCLA) was significantly inhibited in the group given CoQ10 intravenously and 3 times orally, but there was no significant difference in the group given CoQ10 once orally. However, the level of superoxide production by PMN stimulated by phorbol myristate acetate (PMA) was lower in all CoQ10-treated rats than in those given ET only. There was no difference in either peripheral PMN counts or PMN phagocytes between the CoQ10-treated group and the group given ET only. Histologically, the hepatocyte injury in all groups that received CoQ10 was milder than that in the ET-only group. No hepatocyte cytotoxicity by PMN was observed in any group that received CoQ10. These results suggest that both intravenous and oral administration of CoQ10 can modulate the endotoxin-activated PMN, and is useful for preventing hepatocyte injury during ET shock.

Topics: Animals; Coenzymes; Disease Models, Animal; Liver Diseases; Male; Neutrophils; Phagocytosis; Rats; Rats, Wistar; Shock, Septic; Superoxides; Ubiquinone

The protective effects of BMY-21502 (1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone) against cerebral anoxia were investigated using various models in mice, in comparison with those of other cerebroactive drugs. Oral administration of BMY-21502 (10-100 mg/kg) significantly prolonged the survival time in KCN (2.4 mg/kg, i.v.)-induced anoxia. Oxiracetam and idebenone exerted similar but weak protection at doses above 100 mg/kg, p.o. and only at a dose of 100 mg/kg, p.o., respectively. Significant protection by BMY-21502 against moderate hypobaric hypoxia was observed at doses of 30 and 100 mg/kg, p.o. Idebenone (100 and 300 mg/kg, p.o.) significantly prolonged the survival time of mice in this model, but oxiracetam (30-300 mg/kg, p.o.) did not. Oral administration of all of these drugs (BMY-21502, 3-300 mg/kg; Oxiracetam, 100-1000 mg/kg; Idebenone, 100-1000 mg/kg) failed to increase the number of gasps and the duration of gasping in the decapitated head of mice as a complete ischemic model. The anti-anoxic effect of BMY-21502 in the KCN-anoxia model was blocked by pretreatment with scopolamine. These findings suggest that BMY-21502 has an anti-anoxic action superior to those of the other cerebroactive drugs used, and activation of the CNS cholinergic system is involved as one of the causative mechanisms for the anti-anoxic effect of BMY-21502.

Topics: Animals; Atmospheric Pressure; Benzoquinones; Brain Ischemia; Disease Models, Animal; Hypoxia, Brain; Male; Mice; Potassium Cyanide; Psychotropic Drugs; Pyrimidines; Pyrrolidines; Pyrrolidinones; Scopolamine; Ubiquinone

It has been shown that prophylactic administration of ubiquinone protects rats liver from the toxic damage by D-galactosamine both on ultrastructural and on cell levels. Ubiquinone administration prevents necrosis in hepatocytes and preserves their ability for compensatory reactions expressed in activation of protein-synthesis regulating structures in the cell. Ubiquinone decreases hyperfermentemia and hyperbilirubinemia as well as prevents the decrease in liver protein content caused by galactosamine. Ubiquinone exerts an antioxidant effect, blocking the induction of lipid peroxidation both in intact and hepatic rats.

Topics: Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Evaluation, Preclinical; Galactosamine; Liver; Male; Microscopy, Electron; Rats; Ubiquinone

Effects of coenzyme Q9 (25 mg/kg), N6-cyclohexyl adenosine (CHA, 100 micrograms/kg) and their combination were compared in rats with short-term or permanent ligation of the left coronary artery. The following parameters were evaluated in three series of experiments: 1) incidence and duration of ventricular fibrillation and tachycardia during coronary occlusion (10 min) and consecutive reperfusion (5 min); 2) contractility and electrical stability of the heart (ventricular fibrillation threshold) in animals with 2-day myocardial infarction; 3) ischemic myocardial mass after coronary occlusion (5 min) and necrotic tissue mass in 2-day myocardial infarction. The rats were given oral drugs 5 days and 2 hours before the study. All the experiments were performed in open-chest anesthetized (nembutal, 50 mg/kg) rats exposed to ventilation at room air. Both the coenzyme Q9 and CHA significantly reduced the incidence and duration of coronary occlusion and reperfusion arrhythmias, prevented cardiac contractile depression (heart rate.developed pressure) and increased ventricular fibrillation threshold). The effect of coenzyme Q9 was more marked than that of CHA. Coenzyme Q9 substantially reduced necrotic tissue mass while CHA diminished ischemic tissue mass. At the same time the total cardioprotective action of the Q9 + CHA combination was more pronounced than that of them used alone.

Topics: Adenosine; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Heart Arrest, Induced; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Inbred Strains; Ubiquinone

Glucose and steroids have been used in the treatment of children with Reye's syndrome, while carnitine and coenzyme Q10 have been the subject of some recent studies which suggest that these agents may have a role in the treatment of Reye's syndrome and Reye-like syndrome due to margosa oil poisoning. Because of the paucity of causes of Reye's syndrome seen at any one centre, the clinical variability of the disease, and limited knowledge of definite aetiologic factors, controlled clinical trials are not easy to carry out or to interpret in human cases. These caveats were overcome by evaluation of these four treatment modalities in an established margosa-oil-induced animal model of Reye's syndrome. Effectiveness of the treatment modalities was determined from clinical response and histopathologic parameters (grading of light microscopic fatty changes and ultrastructural changes in the hepatocytes). Results show that carnitine per se produces a small improvement in survival, but statistically, more significant benefit is seen with glucose administration. Carnitine plus 10% dextrose appears to produce better results. Evaluation of coenzyme Q10 and carnitine on histopathologic parameters in the liver after a sublethal dose of margosa oil showed no obvious ameliorating effect on liver pathology. Steroids (dexamethasone/methylprednisolone) had no beneficial effects in reducing mortality, affecting glycogen storage or lipid accumulation. Changes in the mitochondria, ribosomes and endoplasmic reticulum were unaltered from the groups treated with margosa oil alone. While glucose and carnitine supplements appear to be beneficial, the other modes of therapy do not seem to hold much promise in the treatment of Reye-like syndrome in the margosa-oil-induced animal model.

Topics: Animals; Carnitine; Coenzymes; Dexamethasone; Disease Models, Animal; Female; Glucose; Glycerides; Methylprednisolone; Mice; Mice, Inbred ICR; Plant Oils; Reye Syndrome; Steroids; Terpenes; Ubiquinone

We studied the effects of coenzyme Q10 (CoQ10) on pulmonary function and chemical mediators in a canine model of hemorrhagic shock. One group received 10 mg/kg of CoQ10 before hemorrhage. During the study, percent change from baseline of peak airway pressure, total lung compliance of the lung and chest wall, and blood lactate levels appeared to be significantly smaller in dogs pretreated with CoQ10 than in controls. Furthermore, CoQ10 was found to maintain blood histamine levels and to attenuate the increase in leukotriene C4. The mechanism of the beneficial effects of CoQ10 in hemorrhagic shock is presently unknown, but our data suggest that it may be useful in the treatment of hemorrhagic shock.

Topics: Airway Resistance; Animals; Blood Gas Analysis; Coenzymes; Disease Models, Animal; Dogs; Hemodynamics; Histamine; Lactates; Lung Compliance; Pulmonary Ventilation; Shock, Hemorrhagic; SRS-A; Ubiquinone

Idebenone, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, at a dose of 100 mg/kg (i.p.) markedly increased the level of 5-hydroxyindole-3-acetic acid (5-HIAA) in several brain regions without affecting monoamine contents in normal rats. In rats with cerebral ischemia, idebenone (10 mg/kg, i.p.) normalized the decreased levels of 5-HIAA in the cerebral cortex, hippocampus, diencephalon and brain stem. A 5-hydroxytryptamine (serotonin, 5-HT) biosynthesis inhibitor, DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) decreased the levels of 5-HT to one-third of the control level 24 h after administration. Idebenone (10, 30, or 100 mg/kg, i.p.), administered 24 h after the treatment with PCPA, accelerated the PCPA-induced 5-HT decreased in the hippocampus, diencephalon and brain stem in a dose-dependent manner. Idebenone (100 mg/kg, i.p.) stimulated the release of 5-HT in the dorsal hippocampus as determined by in vivo differential pulse voltammetry. Idebenone, like p-chloroamphetamine (PCA), stimulated 5-HT release from slices of hippocampus and diencephalon, and the formation of cyclic AMP in a concentration-dependent manner in rat diencephalon slice. This stimulation was almost completely blocked by methysergide, a 5-HT receptor blocker. Idebenone slightly and PCA markedly inhibited 5-HT uptake into hippocampus slices. The mechanism of the 5-HT releasing actions of idebenone in the hippocampal slices may be mediated through endogenous calcium. These results suggest that idebenone has an enhancing effect on the turnover of 5-HT in the hippocampus, diencephalon, and brain stem of rats.

Topics: Animals; Benzoquinones; Biogenic Monoamines; Brain; Brain Ischemia; Cyclic AMP; Disease Models, Animal; Fenclonine; Hippocampus; Hydroxyindoleacetic Acid; Indoles; Male; Quinones; Rats; Rats, Inbred Strains; Serotonin; Ubiquinone

Ischemic insult has been considered a cause of cellular injuries under certain circumstance, such as the disturbance of energy metabolism, the alternation of calcium homeostasis, the production of oxygen radical and the release of lysosomal protease. The present study was designed to clarify the pathophysiological effects of coenzyme Q10 (CoQ10), diltiazem, superoxide dismutase (SOD) and urinastatin on the development and progression of ischemic acute renal failure (IARF) of the rat. At 24 hours after reflow following 45 minutes ischemia, serum urea nitrogen, creatinine and fractional excretion of sodium were 99.3 mg/dl, 3.14 mg/dl, 5.95% respectively, in non-treated IARF rats. Renal ATP content was reduced to 0.91 micrograms/mg. prot. from 10.59 micrograms/mg. prot. at 10 minutes after ischemic insult, and remained at almost the same level throughout the entire 45 minutes ischemia. Although the subsequent blood reflow resulted in the recovery of ATP content, it was up to 50% of normal level at 24 hours after reflow following 45 minutes ischemia. During the ischemic period, the pathological changes were mild, whereas, after reflow, tissue involvement was mainly localized in the S3 segment of the proximal tubule. Major alteration were the loss of brush border, high amplitude swelling of mitochondria with matrical densities and fragmentation of the epithelial cell. At 24 hours after reflow, it was observed that renal function was superior in IARF rats treated with CoQ10, diltiazem, SOD and urinastatin. The treated rats also had higher ATP contents and showed less pathological changes than non-treated rats. Among these inhibitory agents, diltiazem exerted the most reliable effect. From these results, it was concluded that IARF was obviously caused by such pathophysiological mechanisms as mentioned above. Especially, Ca influx into the cells is one of the most important factors on pathogenesis of IARF.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Calcium; Coenzymes; Diltiazem; Disease Models, Animal; Glycoproteins; Kidney; Male; Rats; Rats, Inbred Strains; Superoxide Dismutase; Trypsin Inhibitors; Ubiquinone

Improvement of energy metabolism in ischemic cerebral tissue benefits the therapy of occlusive cerebrovascular disorders. In the present study, the effects of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone) on neurological signs, such as ischemic seizures, lactate and ATP contents of the cerebral cortex, and local cerebral blood flow, were assessed in stroke-prone spontaneously hypertensive rats (SHRSP) with experimentally induced cerebral ischemia. Experimental cerebral ischemia was caused by bilateral carotid artery occlusion (BCAO) in male SHRSP (8-10 weeks old). Pretreatment with idebenone (10-100 mg/kg, p.o.) for 3 or 10 days delayed the onset of ischemic seizure (acute stroke) and prolonged survival time in SHRSP roughly in a dose-dependent manner. When the compound (100 mg/kg, i.p.) was given once 30 min after BCAO, it exerted similar ameliorating effects on the neurological deficits. When idebenone (100 mg/kg for 3 days) was given orally, it did not significantly inhibit the decrease in regional cerebral blood flow induced by BCAO. However, the same treatment markedly inhibited increases in the lactate content and lactate/pyruvate ratio and the decrease in ATP content of the cerebral cortex. The compound did not affect cerebral blood flow in normal rats. These results suggest that idebenone ameliorates the neurological deficits related to cerebral ischemia, and that this effect is mediated by improving cerebral energy metabolism.

Topics: Animals; Benzoquinones; Brain; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Energy Metabolism; Motor Activity; Papaverine; Quinones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Ubiquinone

Cerebral ischemia was induced by a 200-s occlusion of both common carotid arteries in rats in which both vertebral arteries had been permanently cauterized. In the ischemic rats, a significant decrease in acetylcholine (ACh) and a marked increase in choline were observed in the cerebral cortex, hippocampus, striatum, and diencephalon. A slight increase in choline was also observed in the cerebellum and brain stem. Pretreatment with idebenone (10 mg/kg, i.p.) inhibited the decrease in ACh and the increase in choline in the forebrain regions. In addition, the same dose of idebenone inhibited the increments of lactate and free fatty acid contents and tended to inhibit the decrement of the ATP content in the cerebral cortex of the cerebral ischemic rats. These results indicate that idebenone inhibits the alteration of the ACh level and the disruption of membrane phospholipids in the brain of ischemic rats; these effects may be mediated by improved cerebral energy metabolism.

Topics: Acetylcholine; Animals; Benzoquinones; Brain; Brain Ischemia; Choline; Disease Models, Animal; Energy Metabolism; Fatty Acids, Nonesterified; Male; Quinones; Rats; Rats, Inbred Strains; Ubiquinone

This study was undertaken to determine whether pretreatment of the donor rat with coenzyme Q10 (CoQ10) would protect against hepatic ischemia induced for 30 minutes at normothermic body temperature. Fresh liver transplants were used as controls (minus warm ischemia of 30 minutes) and gave a 1-week survival rate of 84.6%. CoQ10 was administered intravenously (10 mg/kg body weight) to the donor rat 1 hour before induction of warm ischemia (group A). In another group (B), the same dose was given intravenously not only to the donor rat but also to the recipient rat 1 hour before grafting. None of the placebo group survived more than 2 days. The 1-week survival rates of the groups pretreated with CoQ10 were 45.5% for group A and 50% for group B. There was no significant difference between groups A and B. A statistically significant difference was demonstrated between the placebo group and both CoQ10-treated groups (p less than 0.05). It was therefore assumed that CoQ10, accumulated in the donor liver, was a primary factor in improving survival. Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum alkaline phosphatase (SALP), total bilirubin, and total protein were measured by means of light and electron microscopic examination of the liver 6 months after transplantation. Long-term-surviving rats with transplanted, ischemically damaged liver that was pretreated with CoQ10 showed a decrease in the activity of SGOT and SGPT and an increase in levels of total protein to the normal range (as well as to those levels exhibited by fresh-liver-transplanted rats) with practically no change in levels of SALP, total bilirubin, or in histologic findings. These results indicate that donor pretreatment with CoQ10 is useful for increasing survival after warm ischemic damage of rat liver grafts.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Coenzymes; Disease Models, Animal; Ischemia; Liver; Liver Transplantation; Male; Mortality; Rats; Rats, Inbred Strains; Ubiquinone

The ceroid lipofuscinoses are inherited lysosomal diseases of children characterized by a fluorescent lipopigment stored in a variety of tissues. Defects in lipid metabolism or the control of lipid peroxidation have been postulated to explain their pathogenesis. In the present study, lipopigment was isolated from the liver of sheep affected with ceroid lipofuscinosis. It was 70% protein, the rest being mainly lipids. These were only one-sixth as fluorescent as total liver lipids, but contained a number of fluorophors. None were major components of the lipopigment or the postulated fluorescent product of lipid peroxidation. Lipopigment lipids included the lysosomal marker bis(monoacylglycero)phosphate that contained 42.9% linoleate and 16.5% linolenate. Lipopigment neutral lipids were dolichol, dolichyl esters, ubiquinone, free fatty acids, and cholesterol, indicative of a lysosomal origin of the lipopigment. Phosphatidylcholine, phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine were present in proportions and with fatty acid profiles typical of lysosomes. No differences were found between the lipids of total control and affected livers, nor the fatty acid profiles of their phosphatidylcholine, phosphatidylethanolamine, or triglycerides. It is concluded that ovine ceroid lipofuscinosis is not a lipidosis, nor does the lipopigment arise from the abnormal peroxidation of lipids. Strong similarities between the lipopigment and the age pigment lipofuscin were noted.

Topics: Animals; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Disease Models, Animal; Dolichols; Fatty Acids; Fluorescence; Liver; Lysophospholipids; Lysosomes; Magnetic Resonance Spectroscopy; Monoglycerides; Neuronal Ceroid-Lipofuscinoses; Phosphatidic Acids; Phospholipids; Pigments, Biological; Proteins; Sheep; Sheep Diseases; Ubiquinone

Previous studies on the lipopigment from the livers of sheep affected with ceroid lipofuscinosis showed that the disease does not involve a defect in lipid metabolism or abnormal lipid peroxidation and that most of the lipopigment was proteinaceous. In this study, lipopigment was isolated from liver, kidney, pancreas, and brain of affected sheep without the use of proteolytic enzymes. Lipopigment from all tissues was two-thirds protein. Modified silver staining after sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a major band of Mr = 14,800, heterogeneous material between Mr = 5,000 and 9,000, and a major band of Mr = 3,500. These compounds did not stain for RNA or carbohydrate and were digested by a nuclease-free protease as expected for protein. They are not normal lysosomal proteins. Lipopigment levels of dolichol, ubiquinone, and cholesterol were consistent with the lipopigment being protein-enriched lysosome-derived cytosomes. The presence of the Mr = 3,500 proteins in whole affected tissue homogenates distinguished them from homogenates of normal tissues. It was concluded that low Mr proteins are specifically stored in ovine ceroid lipofuscinosis and that the ceroid lipofuscinoses may result from inherited defects in lysosomal protein catabolism.

Topics: Animals; Brain Chemistry; Cholesterol; Disease Models, Animal; Dolichols; Electrophoresis, Polyacrylamide Gel; Fatty Acids; Fluorescence; Kidney; Lipids; Liver; Lysosomes; Molecular Weight; Neuronal Ceroid-Lipofuscinoses; Pancreas; Phospholipids; Pigments, Biological; Proteins; Sheep; Sheep Diseases; Ubiquinone

Observations have been made on the effect of intermittent intense sound stimuli, using the CM as an index. Experiments were conducted regarding the effectiveness of the drug CoQ10 in ameliorating the acoustic injury due to this traumatization. The CM was measured by the differential electrode method from the basal turn of the cochlea. The individual differences between animals were monitored using intensity functions. Pure tones at a frequency of 4 kHz were used both for the traumatizing signal and the CM generating signal. Acoustic traumatizing signals lasted 1 min with a 5 min silent interval, and were repeated 10 times. Both the chronic depression and the transient depression of CM were measured after each traumatization. In control animals, the chronic depression progressed in an exponential manner and the transient depression was constant after each stimulation. In CoQ10 treated animals, the chronic depression was milder than that in the control animals. The transient depression was equivalent in the two groups. The effectiveness of CoQ10 on the acoustic injury was discussed on the basis of the results obtained with the present experiment.

Topics: Acoustic Stimulation; Animals; Cochlear Microphonic Potentials; Disease Models, Animal; Evoked Potentials, Auditory; Guinea Pigs; Hearing Loss, Noise-Induced; Ubiquinone

The ultrastructural and erythrokinetic characteristics of vitamin E deficiency in swine were investigated in an effort to evaluate the suitability of the swine disorder as a model of the human congenital dyserythropoietic anemias. The dominant erythrokinetic abnormality in vitamin E deficient pigs, as in the CDAs, is ineffective erythropoiesis. As in some patients with CDA, the activity of a number of erythrocyte enzymes was increased. Distinctive ultrastructual changes previously described in patients with CDA were found in normoblasts from vitamin E deficient pigs. The morphologic, erythrokinetic, biochemical and ultrastructural similarities between vitamin E deficiency in swine and the CDAs in man appear to justify the study of the animal disorder as a model of the human disease. A complete hematologic response was elicited by the administration not only of vitamin E, but also, as in the previous studies of vitamin E deficiency in monkeys, by hexahydrocoenzyme Q4. The partial hematologic response occurring after deletion of tocopherol stripped corn oil from the diet indicates that factors other than the dietary lack of vitamin E are important in the pathogenesis of this disorder.

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Cells; Disease Models, Animal; Iron; Swine; Ubiquinone; Vitamin E; Vitamin E Deficiency

Topics: Animals; Antioxidants; Deficiency Diseases; Disease Models, Animal; Freeze Drying; Kidney; Liver; Muscular Dystrophies; Myocardium; Oxidoreductases; Rabbits; Succinate Dehydrogenase; Ubiquinone; Vitamin E Deficiency