ubiquinone and Neurodegenerative-Diseases

Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment.

Topics: Antioxidants; Cations; Humans; Mitochondria; Neurodegenerative Diseases; Organophosphorus Compounds; Oxidative Stress; Ubiquinone

Coenzyme Q10 (ubiquinone or CoQ10) is a lipid molecule that acts as an electron mobile carrier of the electron transport chain and also contains antioxidant properties. Supplementation of CoQ10 has been very useful to treat mitochondrial diseases. CoQ10 along with its synthetic analogue, idebenone, is used largely to treat various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Friedreich's ataxia and additional brain disease condition like autism, multiple sclerosis, epilepsy, depression, and bipolar disorder, which are related to mitochondrial impairment. In this article, we have reviewed numerous physiological functions of CoQ10 and the rationale for its use in clinical practice in different brain disorders.

Topics: Animals; Antioxidants; Brain Diseases; Humans; Mitochondria; Mitochondrial Diseases; Neurodegenerative Diseases; Ubiquinone

Mitochondria play a vital role in cellular metabolism and are central mediator of intracellular signalling, cell differentiation, morphogenesis and demise. An increasingly higher number of pathologies is linked with mitochondrial dysfunction, which can arise from either genetic defects affecting core mitochondrial components or malfunctioning pathways impairing mitochondrial homeostasis. As such, mitochondria are considered an important target in several pathologies spanning from neoplastic to neurodegenerative diseases as well as metabolic syndromes. In this review we provide an overview of the state-of-the-art in mitochondrial pharmacology, focusing on the novel compounds that have been generated in the bid to correct mitochondrial aberrations. Our work aims to serve the scientific community working on translational medical science by highlighting the most promising pharmacological approaches to target mitochondrial dysfunction in disease.

Topics: Antioxidants; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Dynamics; Neurodegenerative Diseases; Oxidative Phosphorylation; Pyrazines; Ubiquinone

Coenzyme Q

Topics: Biological Availability; Dietary Supplements; Humans; Migraine Disorders; Neoplasms; Neurodegenerative Diseases; Neuromuscular Diseases; Quality of Life; Ubiquinone

Coenzyme Q

Topics: Aging; Ataxia; Cardiovascular Diseases; Dietary Supplements; Humans; Mitochondrial Diseases; Muscle Weakness; Neurodegenerative Diseases; Ubiquinone

Neurodegenerative diseases, namely Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis are becoming one of the main health concerns due to the increasing aging of the world's population. These diseases often share the same biological mechanisms, including neuroinflammation, oxidative stress, and/or protein fibrillation. Recently, there have been many studies published pointing out the possibilities to reduce and postpone the clinical manifestation of these deadly diseases through lifelong consumption of some crucial dietary substances, among which phytochemicals (e.g., polyphenols) and endogenous substances (e.g., acetyl-L-carnitine, coenzyme Q10, n-3 poysaturated fatty acids) showed the most promising results. Another important issue that has been pointed out recently is the availability of these substances to the central nervous system, where they have to be present in high enough concentrations in order to exhibit their neuroprotective properties. As so, such the aim of this review is to summarize the recent findings regarding neuroprotective substances, their mechanisms of action, as well as to point out therapeutic considerations, including their bioavailability and safety for humans.

Topics: Dietary Supplements; Humans; Neurodegenerative Diseases; Ubiquinone

A number of aging-related disorders (ARD) have been related to oxidative stress (OS) and mitochondrial dysfunction (MDF) in a well-established body of literature. Most studies focused on cardiovascular disorders (CVD), type 2 diabetes (T2D), and neurodegenerative disorders. Counteracting OS and MDF has been envisaged to improve the clinical management of ARD, and major roles have been assigned to three mitochondrial cofactors, also termed mitochondrial nutrients (MNs), i.e., α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and carnitine (CARN). These cofactors exert essential-and distinct-roles in mitochondrial machineries, along with strong antioxidant properties. Clinical trials have mostly relied on the use of only one MN to ARD-affected patients as, e.g., in the case of CoQ10 in CVD, or of ALA in T2D, possibly with the addition of other antioxidants. Only a few clinical and pre-clinical studies reported on the administration of two MNs, with beneficial outcomes, while no available studies reported on the combined administration of three MNs. Based on the literature also from pre-clinical studies, the present review is to recommend the design of clinical trials based on combinations of the three MNs.

Topics: Aging; Animals; Antioxidants; Cardiovascular Diseases; Carnitine; Cell Line; Diabetes Mellitus, Type 2; Humans; Mitochondria; Neurodegenerative Diseases; Oxidative Stress; Thioctic Acid; Ubiquinone

Coenzyme Q10 (CoQ10) is a ubiquitous cofactor in the body, operating in the inner mitochondrial membrane, where it plays a vital role in the generation of adenosine triphosphate (ATP) through the electron transport chain (ETC). In addition to this, CoQ10 serves as an antioxidant, protecting the cell from oxidative stress by reactive oxygen species (ROS) as well as maintaining a proton (H

Topics: Animals; Ataxia; Brain; Humans; Mitochondrial Diseases; Muscle Weakness; Neurodegenerative Diseases; Retina; Ubiquinone

Coenzyme Q

Topics: Aging; Animals; Cardiovascular Diseases; Humans; Models, Animal; Neurodegenerative Diseases; Oxidation-Reduction; Renal Insufficiency, Chronic; Ubiquinone; Vitamins

Coenzyme Q10 (CoQ10) is a component of electron transport chain and acts as an antioxidant. It is also used for preventing neurodegeneration against mitochondrial deficiency and oxidative stress. Therefore, CoQ10 has received increasing attention as therapeutic and preventive intervention for neurodegenerative diseases. This review article focuses mainly on the structure of CoQ10, the function of CoQ10 and the relationship between mitochondrial impairment, oxidative stress and neurodegenerative diseases. In addition, the effects of CoQ10 on Alzheimer's disease, Parkinson's disease, and Huntington's disease are also discussed. Finally, future perspectives regarding development of successful treatment for neurodegenerative diseases are proposed.

Topics: Alzheimer Disease; Humans; Huntington Disease; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Ubiquinone

Neurodegenerative movement disorders mainly include Parkinson's disease (PD), atypical parkinsonisms, Huntington's disease (HD), and Friedreich's ataxia (FA). With mitochondrial dysfunction observed in these diseases, mitochondrial enhancement such as creatine, coenzyme Q10 (CoQ10) and its analogues (idebenone and mitoquinone) has been regarded as a potential treatment.. In this paper, we systematically analysed and summarized the efficacy of mitochondrial enhancement in improving motor and other symptoms in neurodegenerative movement disorders.. We searched the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure until September 2013 for eligible randomized controlled trials (RCTs), as well as unpublished and ongoing trials. We calculated the mean differences for continuous data with 95% confidence intervals and pooled the results using a fixed-effect model, if no significant statistical heterogeneity was found (I(2) < 50%).. We included 16 studies with 1,557 randomized patients, which compared creatine, CoQ10 or its analogues with placebo in motor and other symptoms. No significant improvements were found in the motor symptoms of PD, atypical parkinsonisms or HD patients, while only the high dose of idebenone seems to be promising for motor improvement in FA. Certain benefits are found in other symptoms.. There is insufficient evidence to support the use of mitochondrial enhancement in patients with neurodegenerative movement disorders. More well-designed RCTs with large samples are required for further confirmation.

Topics: Animals; Creatine; Dose-Response Relationship, Drug; Humans; Mitochondria; Mitochondrial Diseases; Neurodegenerative Diseases; Organophosphorus Compounds; Randomized Controlled Trials as Topic; Ubiquinone

Coenzyme Q10 is a small electron carrier of the respiratory chain with antioxidant properties, widely used for the treatment of mitochondrial disorders. Mitochondrial diseases are neuromuscular disorders caused by impairment of the respiratory chain and increased generation of reactive oxygen species. Coenzyme Q10 supplementation is fundamental in patients with primary coenzyme Q10 deficiency. Furthermore, coenzyme Q10 and its analogues, idebenone and mitoquinone (or MitoQ), have been also used in the treatment of other neurogenetic/neurodegenerative disorders. In Friedreich ataxia idebenone may reduce cardiac hypertrophy and, at higher doses, also improve neurological function. These compounds may also play a potential role in other conditions which have been linked to mitochondrial dysfunction, such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and Alzheimer disease. This review introduces mitochondrial disorders and Friedreich ataxia as two paradigms of the tight links existing between oxidative stress, respiratory chain dysfunction and neurodegeneration, and focuses on current and emerging therapeutic uses of coenzyme Q10 and idebenone in neurology.

Topics: Animals; Humans; Micronutrients; Mitochondria; Mitochondrial Diseases; Molecular Targeted Therapy; Neurodegenerative Diseases; Ubiquinone

Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.

Topics: Animals; Humans; Mitochondrial Diseases; Neurodegenerative Diseases; Neuromuscular Diseases; Ubiquinone

Coenzyme Q (Q) is a key component for bioenergetics and antioxidant protection in the cell. During the last years, research on diseases linked to Q-deficiency has highlighted the essential role of this lipid in cell physiology. Q levels are also affected during aging and neurodegenerative diseases. Therefore, therapies based on dietary supplementation with Q must be considered in cases of Q deficiency such as in aging. However, the low bioavailability of dietary Q for muscle and brain obligates to design new mechanisms to increase the uptake of this compound in these tissues. In the present review we show a complete picture of the different functions of Q in cell physiology and their relationship to age and age-related diseases. Furthermore, we describe the problems associated with dietary Q uptake and the mechanisms currently used to increase its uptake or even its biosynthesis in cells. Strategies to increase Q levels in tissues are indicated.

Topics: Aging; Animals; Antioxidants; Biological Transport; Brain; Diet; Dietary Supplements; Energy Metabolism; Lipids; Muscles; Neurodegenerative Diseases; Rats; Ubiquinone

Coenzyme Q(10) (CoQ(10)) is found in blood and in all organs. CoQ(10) deficiencies are due to autosomal recessive mutations, ageing-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer and muscular and cardiovascular diseases have been associated with low CoQ(10) levels, as well as different ataxias and encephalomyopathies.. We review the efficacy of a variety of commercial formulations which have been developed to solubilise CoQ(10) and promote its better absorption in vivo, and its use in the therapy of pathologies associated with low CoQ(10) levels, with emphasis in the results of the clinical trials. Also, we review the use of its analogues idebenone and MitoQ.. This review covers the most relevant aspects related with the therapeutic use of CoQ(10), including existing formulations and their effects on its bioavailability.. CoQ(10) does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ(10) absorption. Oral CoQ(10) is a viable antioxidant strategy in many diseases, providing a significant to mild symptomatic benefit. Idebenone and MitoQ are promising substitutive CoQ(10)-related drugs which are well tolerated and safe.

Topics: Animals; Cardiovascular Diseases; Chemistry, Pharmaceutical; Humans; Neurodegenerative Diseases; Ubiquinone

The authors summarized the evidence supporting neuroprotection based on the data available in the literature. In vivo and in vitro studies have indicated that many compounds can decrease neurodegeneration, excitotoxicity, oxidative stress, protein aggregation, disturbance of Ca2+ homeostasis and compensate the energy impairment. Selegiline, rasagiline, dopamine agonists and other molecules (ubiquinone, kynurenic acid, tocopherol, creatine, glatiramer acetate) exert neuroprotective effects in preclinical studies. Much less clinical data are available regarding neuroprotection in different neurological disorders. In this review, such preclinical and clinical evidences are summarized.

Topics: Animals; Creatine; Dopamine Agonists; Glatiramer Acetate; Humans; Indans; Kynurenic Acid; Micronutrients; Nerve Degeneration; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Peptides; Selegiline; Tocopherols; Ubiquinone

Coenzyme Q10 (CoQ10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals produced during oxidative phosphorylation in the inner mitochondrial membrane. Oxidative stress, resulting in glutathione loss and oxidative DNA and protein damage, has been implicated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Experimental studies in animal models suggest that CoQ10 may protect against neuronal damage that is produced by ischemia, atherosclerosis and toxic injury. Though most have tended to be pilot studies, there are published preliminary clinical trials showing that CoQ10 may offer promise in many brain disorders. For example, a 16-month randomized, placebo-controlled pilot trial in 80 subjects with mild Parkinson's disease found significant benefits for oral CoQ10 1,200 mg/day to slow functional deterioration. However, to date, there are no published clinical trials of CoQ10 in Alzheimer's disease. Available data suggests that oral CoQ10 seems to be relatively safe and tolerated across the range of 300-2,400 mg/day. Randomized controlled trials are warranted to confirm CoQ10's safety and promise as a clinically effective neuroprotectant.

Topics: Alzheimer Disease; Animals; Antioxidants; Brain; Coenzymes; Humans; Huntington Disease; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Parkinson Disease; Randomized Controlled Trials as Topic; Ubiquinone; 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

The etiology of several neurodegenerative disorders is thought to involve impaired mitochondrial function and oxidative stress. Coenzyme Q-10 (CoQ10) acts both as an antioxidant and as an electron acceptor at the level of the mitochondria. In several animal models of neurodegenerative diseases including amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease, CoQ10 has shown beneficial effects. Based on its biochemical properties and the effects in animal models, several clinical trials evaluating CoQ10 have been undertaken in many neurodegenerative diseases. CoQ10 appears to be safe and well tolerated, and several efficacy trials are planned.

Topics: Aging; Amyotrophic Lateral Sclerosis; Animals; Clinical Trials as Topic; Humans; Huntington Disease; Models, Biological; Mutation; Neurodegenerative Diseases; Parkinson Disease; Time Factors; Treatment Outcome; Ubiquinone

Mitochondrial disorders are increasingly acknowledged as a major category in clinical neurology. In this review we highlight the most recent advances in the field, including the characterization of new disease genes, new physiopathological insights, and the role of mitochondrial dysfunction in neurodegeneration.. Substantial progress has been made on the genetic basis and pathogenic mechanisms in disorders associated with altered mitochondrial DNA stability and expression. These defects include a wide spectrum of neurological conditions caused by genetic abnormalities of the mitochondrial replication and translation machineries, and of the metabolic pathways controlling the nucleotide supply to organelles, cells and tissues. Another relevant contribution has been given to the molecular dissection of coenzyme Q deficiency, a clinically heterogeneous, potentially treatable condition, thanks to the biochemical and genetic characterization of the first defects in coenzyme Q biosynthesis. Finally, the genetic determinants controlling the penetrance of mitochondrial disorders, as well as the role of mitochondrial dysfunction in neurodegenerative conditions such as Parkinson's and Huntington's diseases, have been investigated in both patients and animal models.. The dual genetic contribution controlling mitochondrial biogenesis, and the intricacy and universality of the metabolic pathways operating in the mitochondrion explain the complexity of what is now known as 'mitochondrial medicine'.

Topics: DNA, Mitochondrial; Genetic Predisposition to Disease; Humans; Mitochondria; Mitochondrial Diseases; Mutation; Neurodegenerative Diseases; Oxidative Phosphorylation; Ubiquinone

Available data on the absorption, metabolism and pharmacokinetics of coenzyme Q10 (CoQ10) are reviewed in this paper. CoQ10 has a fundamental role in cellular bioenergetics. CoQ10 is also an important antioxidant. Because of its hydrophobicity and large molecular weight, absorption of dietary CoQ10 is slow and limited. In the case of dietary supplements, solubilized CoQ10 formulations show enhanced bioavailability. The T(max) is around 6 h, with an elimination half-life of about 33 h. The reference intervals for plasma CoQ10 range from 0.40 to 1.91 micromol/l in healthy adults. With CoQ10 supplements there is reasonable correlation between increase in plasma CoQ10 and ingested dose up to a certain point. Animal data show that CoQ10 in large doses is taken up by all tissues including heart and brain mitochondria. This has implications for therapeutic applications in human diseases, and there is evidence for its beneficial effect in cardiovascular and neurodegenerative diseases. CoQ10 has an excellent safety record.

Topics: Animals; Antioxidants; Cardiovascular Diseases; Dietary Supplements; Humans; Neurodegenerative Diseases; Ubiquinone

Coenzyme Q10 (ubiquinone) is a naturally occurring compound widely distributed in animal organisms and in humans. The primary compounds involved in the biosynthesis of ubiquinone are 4-hydroxybenzoate and the polyprenyl chain. An essential role of coenzyme Q10 is as an electron carrier in the mitochondrial respiratory chain. Moreover, coenzyme Q10 is one of the most important lipophilic antioxidants, preventing the generation of free radicals as well as oxidative modifications of proteins, lipids, and DNA, it and can also regenerate the other powerful lipophilic antioxidant, alpha-tocopherol. Antioxidant action is a property of the reduced form of coenzyme Q10, ubiquinol (CoQ10H2), and the ubisemiquinone radical (CoQ10H*). Paradoxically, independently of the known antioxidant properties of coenzyme Q10, the ubisemiquinone radical anion (CoQ10-) possesses prooxidative properties. Decreased levels of coenzyme Q10 in humans are observed in many pathologies (e.g. cardiac disorders, neurodegenerative diseases, AIDS, cancer) associated with intensive generation of free radicals and their action on cells and tissues. In these cases, treatment involves pharmaceutical supplementation or increased consumption of coenzyme Q10 with meals as well as treatment with suitable chemical compounds (i.e. folic acid or B-group vitamins) which significantly increase ubiquinone biosynthesis in the organism. Estimation of coenzyme Q10 deficiency and efficiency of its supplementation requires a determination of ubiquinone levels in the organism. Therefore, highly selective and sensitive methods must be applied, such as HPLC with UV or coulometric detection.

Topics: Animals; Antioxidants; Coenzymes; Cytoprotection; Free Radicals; Humans; Mitochondria; Neoplasms; Neurodegenerative Diseases; Ubiquinone

A number of strategies using the nutritional approach are emerging for the protection of the brain from damage caused by metabolic toxins, age, or disease. Neural dysfunction and metabolic imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an alternative and early intervention approach that may prevent further damage. Various models have been developed to study the impact of metabolism on brain function. These have also proven useful in expanding our understanding of neurodegeneration processes. For example, the metabolic compromise induced by inhibitors such as 3-nitropropionic acid (3-NPA), rotenone, and 1-methyl-4-phenylpyridinium (MPP+) can cause neurodegeneration in animal models and these models are thought to simulate the processes that may lead to diseases such as Huntington's and Parkinson's diseases. These inhibitors of metabolism are thought to selectively kill neurons by inhibiting various mitochondrial enzymes. However, the eventual cell death is attributed to oxidative stress damage of selectively vulnerable cells, especially highly differentiated neurons. Various studies indicate that the neurotoxicity resulting from these types of metabolic compromise is related to mitochondrial dysfunction and may be ameliorated by metabolic modifiers such as L-carnitine (L-C), creatine, and coenzyme Q10, as well as by antioxidants such as lipoic acid, vitamin E, and resveratrol. Mitochondrial function and cellular metabolism are also affected by the dietary intake of essential polyunsaturated fatty acids (PUFAs), which may regulate membrane composition and influence cellular processes, especially the inflammatory pathways. Cellular metabolic function may also be ameliorated by caloric restriction diets. L-C is a naturally occurring quaternary ammonium compound that is a vital cofactor for the mitochondrial entry and oxidation of fatty acids. Any factors affecting L-C levels may also affect ATP levels. This endogenous compound, L-C, together with its acetyl ester, acetyl-L-carnitine (ALC), also participates in the control of the mitochondrial acyl-CoA/CoA ratio, peroxisomal oxidation of fatty acids, and production of ketone bodies. A deficiency of carnitine is known to have major deleterious effects on the CNS. We have examined L-C and its acetylated derivative, ALC, as potential neuroprotective compounds using various known metabolic inhibitors, as well as against drugs of abuse such as methamphetamine.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antimetabolites; Antioxidants; Carnitine; Central Nervous System Stimulants; Coenzymes; Energy Metabolism; Fatty Acids, Unsaturated; Glucose; Humans; Methamphetamine; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress; Ubiquinone

Coenzyme Q (ubiquinone, 2-methyl-5,6-dimethoxy-1,4-benzoquinone), soluble natural fat quinine, is crucial to optimal biological function. The coenzyme Q molecule has amphipathic (biphasic) properties due to the hydrophilic benzoquinone ring and the lipophilic poly isoprenoid side-chain. The nomenclature of coenzyme Q-n is based on the amount of isoprenoid units attached to 6-position on the benzoquinone ring. It was demonstrated that coenzyme Q, in addition to its role in electron transport and proton transfer in mitochondrial and bacterial respiration, acts in its reduced form (ubiquinol) as an antioxidant. Coenzyme Q-10 functions as a lipid antioxidant regulating membrane fluidity, recycling radical forms of vitamin C and E, and protecting membrane phospholipids against peroxidation. The antioxidant property, high degree of hydrophobicity and universal occurrence in biological system, suggest an important role for ubiquinone and ubiquinol in cellular defense against oxidative damage. Coenzyme Q-10 is a ubiquitous and endogenous lipid-soluble antioxidant found in all organisms. Neurodegenerative disorders, cancer, cardiovascular diseases and diabetes mellitus and especially aging and Alzheimer's disease exhibit altered levels of ubiquinone or ubiquinol, indicating their likely crucial role in the pathogenesis and cellular mechanisms of these ailments. This review is geared to discuss the biological effect of coenzyme Q with an emphasis on its impact in initiation, progression, treatment and prevention of neurodegenerative, cardiovascular and carcinogenic diseases.

Topics: Aging; Animals; Antioxidants; Cardiovascular Diseases; Diabetes Mellitus; Humans; Lipid Peroxidation; Neoplasms; Neurodegenerative Diseases; Oxidative Stress; Ubiquinone

Topics: Animals; Antioxidants; Brain; Coenzymes; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Ubiquinone

Ubiquitinated inclusions and selective neuronal cell death are considered the pathological hallmarks of Parkinson's disease and other neurodegenerative diseases. Recent genetic, pathological and biochemical evidence suggests that dysfunction of ubiquitin-dependent protein degradation by the proteasome might be a contributing, if not initiating factor in the pathogenesis of these diseases. In neuronal cell culture models inhibition of the proteasome leads to cell death and formation of fibrillar ubiquitin and alpha-synuclein-positive inclusions, thus modeling some aspects of Lewy body diseases. The processes of inclusion formation and neuronal cell death share some common mechanisms, but can also be dissociated at a certain level.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Cell Death; Humans; Inclusion Bodies; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Parkinson Disease; Synucleins; Ubiquinone

Coenzyme Q(10) (ubiquinone), which serves as the electron acceptor for complexes I and II of the mitochondrial electron transport chain and also acts as an antioxidant, has the potential to be a beneficial agent in neurodegenerative diseases in which there is impaired mitochondrial function and/or excessive oxidative damage. Substantial data have accumulated to implicate these processes in the pathogenesis in certain neurodegenerative disorders, including Parkinson's disease, Huntington's disease and Friedreich's ataxia. Although no study to date has unequivocally demonstrated that coenzyme Q(10) can slow the progression of a neurodegenerative disease, recent clinical trials in these three disorders suggest that supplemental coenzyme Q(10) can slow the functional decline in these disorders, particularly Parkinson's disease.

Topics: Animals; Antioxidants; Clinical Trials as Topic; Coenzymes; Humans; Neurodegenerative Diseases; Ubiquinone

Alpha-synuclein belongs to a family of vertebrate proteins, encoded by three different genes: alpha, ss, and gamma. The protein has become of interest to the neuroscience community in the last few years after the discovery that a mutation in the alpha-synuclein gene is associated with familial autosomal-dominant early-onset forms of Parkinson Disease. However, it is not yet clear how the protein is involved in the disease. Several studies have suggested that alpha-synuclein plays a role in neurotransmitter release and synaptic plasticity. This hypothesis might help elucidate how alpha-synuclein malfunctioning contributes to the development of a series of disorders known as synucleinopathies.

Topics: alpha-Synuclein; Animals; Environment; Humans; Mutation; Nerve Tissue Proteins; Neurodegenerative Diseases; Parkinson Disease; Synapses; Synaptic Transmission; Synucleins; Ubiquinone; Ubiquitin-Protein Ligases

This review focuses on the mechanisms of action and the injurious effect of complex I inhibitors, of which 1-methyl-4-phenylpyridinium ion (MPP(+)) is a well studied example. These compounds can be divided into two groups, i.e. competitive inhibitors with respect to ubiquinone, such as piericidine A, and non-competitive inhibitors such as rotenone. Complex I inhibitors such as MPP(+) have been reported to induce anatomical, behavioral, and biochemical changes similar to those seen in Parkinson's disease, which is characterized by nigrostriatal dopaminergic neuro-degeneration. Spectroscopic analyses and structure-activity relationship studies have indicated that the V-shaped structure of the rotenone molecule is critical for binding to the rotenone binding site on complex I. Many isoquinoline derivatives, some of them endogenous, are also complex I inhibitors. Many lines of evidence show that complex I inhibitors elicit neuronal cell death. Recently, it was reported that chronic and systemic exposure to low-dose rotenone reproduces the features of Parkinson's disease. This work further focused attention on compounds acting on mitochondria, such as MPP(+). In Guadeloupe, the French West Indies, patients with atypical parkinsonism or progressive supranuclear palsy are frequently encountered. These diseases seem to be associated with ingestion of tropical herbal teas or tropical fruits of the Annonaceae family, which contain complex I inhibitors such as benzylisoquinoline derivatives and acetogenins. Complex I inhibitors may not simply result in reactive oxygen species generation or ATP exhaustion, but may influence complex downstream signal transduction processes. An understanding of these changes would throw light on the ways in which complex I inhibitors induce a wide range of abnormalities.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Electron Transport; Humans; Isoquinolines; Mitochondria; Neurodegenerative Diseases; Neurons; Parkinson Disease, Secondary; Rotenone; Ubiquinone; Uncoupling Agents

ECTO-NOX (because of their cell surface location) proteins comprise a family of NAD(P)H oxidases of plants and animals that exhibit both oxidative and protein disulfide isomerase-like activities. The two biochemical activities, hydroquinone [NAD(P)H] oxidation and protein disulfide--thiol interchange alternate, a property unprecedented in the biochemical literature. A tumor-associated ECTO-NOX (tNOX) is cancer-specific and drug-responsive. The constitutive ECTO-NOX (CNOX) is ubiquitous and refractory to drugs. The physiological substrate for the oxidative activity appears to be hydroquinones of the plasma membrane such as reduced coenzyme Q10. ECTO-NOX proteins are growth-related and drive cell enlargement. Also indicated are roles in aging and in neurodegenerative diseases. The regular pattern of oscillations appears to be related to alpha-helix-beta-structure transitions and serves biochemical core oscillator of the cellular biological clock. Period length is independent of temperature (temperature compensated) and synchrony is achieved through entrainment.

Topics: Aging; Amino Acid Motifs; Amino Acid Sequence; Animals; Biological Clocks; Cell Division; Cell Membrane; Coenzymes; Humans; Models, Biological; Molecular Sequence Data; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Neoplasms; Neurodegenerative Diseases; Oxygen; Prions; Sequence Homology, Amino Acid; Temperature; Time Factors; Ubiquinone

Topics: Animals; Brain; Humans; Metallothionein; Mitochondria; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Phosphorylation; Parkinson Disease; Ubiquinone

Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.

Topics: Animals; Antioxidants; Coenzymes; Cytoprotection; Dietary Supplements; Humans; Mice; Mice, Transgenic; Neurodegenerative Diseases; Ubiquinone

Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain as well as an important antioxidant. Previous studies have suggested that it may exert therapeutic effects in patients with known mitochondrial disorders. We investigated whether it can exert neuroprotective effects in a variety of animal models. We have demonstrated that CoQ10 can protect against striatal lesions produced by both malonate and 3-nitropropionic acid. It also protects against MPTP toxicity in mice. It extended survival in a transgenic mouse model of amyotrophic lateral sclerosis. We demonstrated that oral administration can increase plasma levels in patients with Parkinson's disease. Oral administration of CoQ10 significantly decreased elevated lactate levels in patients with Huntington's disease. These studies therefore raise the prospect that administration of CoQ10 may be useful for the treatment of neurodegenerative diseases.

Topics: Administration, Oral; Animals; Antioxidants; Coenzymes; Humans; Huntington Disease; Lactates; Mice; Mice, Transgenic; Neurodegenerative Diseases; Parkinson Disease; 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

The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases.. Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography.. We detected a statistically significant decrease (by 3-5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson's disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)].. Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated.

Topics: Aged; Aged, 80 and over; Aging; Cerebellum; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Ubiquinone

Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) prion causes the rare human disorder Creutzfeldt-Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T-YFP) and TgM83(+/-) mice expressing α-synuclein (A53T). The TgM83(+/-) mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83(+/+) mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83(+/-) mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T-YFP in cultured cells, whereas none of six Parkinson's disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

Topics: Aged; alpha-Synuclein; Animals; Brain; Exons; Female; HEK293 Cells; Humans; Immunohistochemistry; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Parkinsonian Disorders; Phosphorylation; Polymorphism, Single Nucleotide; Prions; Ubiquinone

Neuropathy and neurocognitive deficits are common among chronic alcohol users, which are believed to be associated with mitochondrial dysfunction in the brain. The specific type of brain mitochondrial respiratory chain complexes (mRCC) that are adversely affected by alcohol abuse has not been studied. Thus, we examined the alterations of mRCC in freshly isolated mitochondria from mice brain that were pair-fed the ethanol (4% v/v) and control liquid diets for 7-8 weeks. We observed that alcohol intake severely reduced the levels of complex I and V. A reduction in complex I was associated with a decrease in carnitine palmitoyltransferase 1 (cPT1) and cPT2 levels. The mitochondrial outer (cPT1) and inner (cPT2) membrane transporter enzymes are specialized in acylation of fatty acid from outer to inner membrane of mitochondria for ATP production. Thus, our results showed that alterations of cPT1 and cPT2 paralleled a decrease β-oxidation of palmitate and ATP production, suggesting that impairment of substrate entry step (complex I function) can cause a negative impact on ATP production (complex V function). Disruption of cPT1/cPT2 was accompanied by an increase in cytochrome C leakage, while reduction of complex I and V paralleled a decrease in depolarization of mitochondrial membrane potential (ΔΨ, monitored by JC-1 fluorescence) and ATP production in alcohol intake. We noted that acetyl-L-carnitine (ALC, a cofactor of cPT1 and cPT2) prevented the adverse effects of alcohol while coenzyme Q10 (CoQ10) was not very effective against alcohol insults. These results suggest that understanding the molecular, biochemical, and signaling mechanisms of the CNS mitochondrial β-oxidation such as ALC can mitigate alcohol related neurological disorders.

Topics: Adenosine Triphosphate; Alcoholism; Animals; Brain; CA1 Region, Hippocampal; Carnitine O-Palmitoyltransferase; Cytochromes c; Electron Transport Chain Complex Proteins; Ethanol; Male; Membrane Potential, Mitochondrial; Mice; Mitochondria; Neurodegenerative Diseases; Oxidation-Reduction; Synaptic Transmission; Time Factors; Ubiquinone

Two new aza analogues of the neuroprotective agent idebenone have been synthesized and characterized. Their antioxidant activity, and ability to augment ATP levels have been evaluated in several different cell lines having suboptimal mitochondrial function. Both compounds were found to be good ROS scavengers, and to protect the cells from oxidative stress induced by glutathione depletion. The compounds were more effective than idebenone in neurodegenerative disease cells. These novel pyrimidinol derivatives were also shown to augment ATP levels in coenzyme Q(10)-deficient human lymphocytes. The more lipophilic side chains attached to the pyrimidinol redox core in these compounds resulted in less inhibition of the electron transport chain and improved antioxidant activity.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Cattle; Cell Line; Cell Survival; Drug Design; Glutathione; Humans; Lymphocytes; Mitochondria; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Neurodegenerative Diseases; Neuroprotective Agents; Pyrimidines; Reactive Oxygen Species; Ubiquinone

Coenzyme Q(10) (CoQ(10)) is present in humans in both the reduced (ubiquinol, CoQ(10)H(2)) and oxidized (ubiquinone, CoQ(10)) forms. CoQ(10) is an essential cofactor in mitochondrial oxidative phosphorylation, and is necessary for ATP production. Total, reduced and oxidized CoQ(10) levels in skeletal muscle of 148 children were determined by HPLC coupled with electrochemical detection, and we established three level thresholds for total CoQ(10) in muscle. We defined as "severe deficiency", CoQ(10) levels falling in the range between 0.82 and 4.88 μmol/g tissue; as "intermediate deficiency", those ranging between 5.40 and 9.80 μmol/g tissue, and as "mild deficiency", the amount of CoQ(10) included between 10.21 and 19.10 μmol/g tissue. Early identification of CoQ(10) deficiency has important implications in children, not only for those with primary CoQ(10) defect, but also for patients with neurodegenerative disorders, in order to encourage earlier supplementation with this agent also in mild and intermediate deficiency.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Chromatography, High Pressure Liquid; Electrochemical Techniques; Female; Humans; Infant; Male; Muscle, Skeletal; Neurodegenerative Diseases; Oxidation-Reduction; Reference Values; Ubiquinone

Byproducts of oxidative metabolic reactions could play a role in the pathogenesis of several neurodegenerative diseases (ND) including Alzheimer's disease (AD). We designed a study aimed at investigating a large set of oxidative and antioxidant markers in a sample of patients affected by different forms of dementia or memory impairment.. Serum levels of coenzyme Q(10), malondialdehyde (MDA), the total, oxidized and reduced forms of glutathione (GStot, GSSG and GSH, respectively), reactive oxygen species, anti-oxidized low-density lipoprotein antibodies and antioxidant power (PAO) were investigated in patients affected by AD, mild cognitive impairment, dementia with Lewy bodies and Parkinson's disease with dementia. The patient sample (n = 66) was compared with healthy subjects (HC; n = 62), and a comparison across pathological subgroups was also performed. A multivariate logistic regression model was implemented in order to calculate an algorithm model for predicting the risk of developing a neurodegenerative disorder.. The comparison between the memory deficit (MD) group and HC showed a significant difference for MDA (MD: 6.3 ± 2.8 μg/l; HC: 9.1 ± 4.9 μg/l; p = 1.7 × 10(-6)), GStot (MD: 260.4 ± 62.6 mg/l; HC: 306.5 ± 60.7 mg/l; p = 2.2 × 10(-5)), GSH (MD: 208.9 ± 68.4 mg/l; HC: 295.3 ± 101.3 mg/l; p = 2.2 × 10(-7)) and PAO (MD: 1,066.5 ± 247.7 μmol; HC: 954.9 ± 200.4 μmol; p = 0.8 × 10(-3)). By contrast, no differences in the levels of the studied markers were detected across the different forms of ND. An older age, higher levels of PAO, lower levels of GSH and MDA and the use of cardiovascular or antidepressant drugs were the most important factors associated with the carrier ship of neurodegenerative disorder.. To our knowledge, this is the first study reporting similar oxidative imbalance in different forms of memory impairment, regardless of the specific etiology. Low GSH levels could be considered as a favorable factor in ND; at the same time it could be suggested that higher levels of PAO represent a counteracting mechanism against an increased oxidative stress. The association between vascular risk factors, depressive status and cognitive impairment is in line with findings in the literature.

Topics: Aged; Aged, 80 and over; Antibodies; Case-Control Studies; Cognition Disorders; Female; Glutathione; Humans; Lipoproteins, LDL; Logistic Models; Male; Malondialdehyde; Memory Disorders; Neurodegenerative Diseases; Oxidation-Reduction; Oxidative Stress; Pilot Projects; Reactive Oxygen Species; Ubiquinone

Mitochondria-related oxidative damage is a primary event in aging and age-related neurodegenerative disorders. Some dietary treatments, such as antioxidant supplementation or the enrichment of mitochondrial membranes with less oxidizable fatty acids, reduce lipid peroxidation and lengthen life span in rodents. This study compares life-long feeding on monounsaturated fatty acids (MUFAs), such as virgin olive oil, and n-6 polyunsaturated fatty acids, such as sunflower oil, with or without coenzyme Q₁₀ supplementation, with respect to age-related molecular changes in rat brain mitochondria. The MUFA diet led to diminished age-related phenotypic changes, with lipoxidation-derived protein markers being higher among the older animals, whereas protein carbonyl compounds were lower. It is noteworthy that the MUFA diet prevented the age-related increase in levels of mitochondrial DNA deletions in the brain mitochondria from aged animals. The findings of this study suggest that age-related oxidative stress is related, at the mitochondrial level, to other age-related features such as mitochondrial electron transport and mtDNA alterations, and it can be modulated by selecting an appropriate dietary fat type and/or by suitable supplementation with low levels of the antioxidant/electron carrier molecule coenzyme Q.

Topics: Aging; alpha-Tocopherol; Animals; Brain; Dietary Fats, Unsaturated; Dietary Supplements; DNA, Mitochondrial; Fatty Acids, Monounsaturated; Food, Formulated; Humans; Lipid Peroxidation; Male; Mitochondria; Mitochondrial Membranes; Neurodegenerative Diseases; Olive Oil; Oxidative Stress; Plant Oils; Polymerase Chain Reaction; Rats; Rats, Wistar; Sequence Deletion; Sunflower Oil; Ubiquinone; Vitamins

Topics: Antioxidants; Humans; Neurodegenerative Diseases; Oxidative Stress; Ubiquinone

The effects of decylubiquinone, a ubiquinone analogue, on mitochondrial function and inhibition thresholds of the electron transport chain enzyme complexes in synaptosomes were investigated. Decylubiquinone increased complex I/III and complex II/III activities by 64 and 80%, respectively, and attenuated reductions in oxygen consumption at high concentrations of the complex III inhibitor myxothiazol. During inhibition of complex I, decylubiquinone attenuated reductions in synaptosomal oxygen respiration rates, as seen in the complex I inhibition threshold. Decylubiquinone increased the inhibition thresholds of complex I/III, complex II/III, and complex III over oxygen consumption in the nerve terminal by 25-50%, when myxothiazol was used to inhibit complex III. These results imply that decylubiquinone increases mitochondrial function in the nerve terminal during complex I or III inhibition. The potential benefits of decylubiquinone in diseases where complex I, I/III, II/III, or III activities are deficient are discussed.

Topics: Animals; Antimycin A; Electron Transport; Female; Methacrylates; Mitochondria; Models, Biological; Neurodegenerative Diseases; Oxygen Consumption; Rats; Rats, Wistar; Rotenone; Synaptosomes; Thiazoles; Ubiquinone; Uncoupling Agents

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

Mitochondria are key regulators of cell viability and provide essential functions that protect against neurodegenerative disease. To develop a model for mitochondrial-dependent neurodegeneration in Caenorhabditis elegans, we used RNA interference (RNAi) and genetic ablation to knock down expression of enzymes in the Coenzyme Q (CoQ) biosynthetic pathway. CoQ is a required component of the ATP-producing electron transport chain in mitochondria. We found that reduced levels of CoQ result in a progressive uncoordinated (Unc) phenotype that is correlated with the appearance of degenerating GABA neurons. Both the Unc and degenerative phenotypes emerge during late larval development and progress in adults. Neuron classes in motor and sensory circuits that use other neurotransmitters (dopamine, acetylcholine, glutamate, serotonin) and body muscle cells were less sensitive to CoQ depletion. Our results indicate that the mechanism of GABA neuron degeneration is calcium-dependent and requires activation of the apoptotic gene, ced-4 (Apaf-1). A molecular cascade involving mitochondrial-initiated cell death is also consistent with our finding that GABA neuron degeneration requires the mitochondrial fission gene, drp-1. We conclude that the cell selectivity and developmental progression of CoQ deficiency in C. elegans indicate that this model may be useful for delineating the role of mitochondrial dysfunction in neurodegenerative disease.

Topics: Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Caenorhabditis elegans; Calcium; gamma-Aminobutyric Acid; Mitochondrial Diseases; Neurodegenerative Diseases; Neurons; Ubiquinone

Coenzyme Q10 is an essential cofactor of the electron transport chain and is an antioxidant. We examined the effects of oral feeding with coenzyme Q10 in young animals on brain concentrations. Feeding with coenzyme Q10 at a dose of 200 mg/kg for 1-2 months in young rats resulted in significant increases in liver concentrations, however, there was no significant increase in brain concentrations of either reduced- or total coenzyme Q10 levels. Nevertheless there was a reduction in malonate-induced increases in 2,5 dihydroxybenzoic acid to salicylate, consistent with an antioxidant effect. In other studies we found that oral administration of coenzyme Q10 significantly reduced increased concentrations of lactate in the occipital cortex of Huntington's disease patients. These findings suggest that coenzyme Q10 might be useful in treating neurodegenerative diseases.

Topics: Administration, Oral; Animals; Antioxidants; Brain; Coenzymes; Corpus Striatum; Electron Transport; Gentisates; Humans; Hydroxybenzoates; Injections; Liver; Male; Malonates; Neurodegenerative Diseases; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Salicylates; Salicylic Acid; Ubiquinone