coenzyme-q10 and idebenone

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

Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012.. To assess the effects of pharmacological treatments for Friedreich ataxia.. On 29 February 2016 we searched The Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE and CINAHL Plus. On 7 March 2016 we searched ORPHANET and TRIP. We also checked clinical trials registers for ongoing studies.. We considered randomised controlled trials (RCTs) or quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed Friedreich ataxia. The primary outcome was change in a validated Friedreich ataxia neurological score after 12 months. Secondary outcomes were changes in cardiac status as measured by magnetic resonance imaging or echocardiography, quality of life, mild and serious adverse events, and survival. We excluded trials of duration shorter than 12 months.. Three review authors selected trials and two review authors extracted data. We obtained missing data from the two RCTs that met our inclusion criteria. We collected adverse event data from included studies. We used standard methodological procedures expected by Cochrane.. We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion.In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence).The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low.There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis.. Low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration.

Topics: Antioxidants; Friedreich Ataxia; Heart; Humans; Hypertrophy, Left Ventricular; Randomized Controlled Trials as Topic; Rare Diseases; Ubiquinone; Ultrasonography; Vitamin E

Coenzyme Q10 is a ubiquitous component of cellular membranes and belongs to the class of benzoquinones that mainly differ with regards to the length and composition of their hydrophobic tail. The characteristic quinone group can accept electrons from various biological sources and is converted by a one electron transfer to the unstable semiquinone or by a two electron transfer to the more stable hydroquinone. This feature makes CoQ10 the bona fide cellular electron transfer molecule within the mitochondrial respiratory chain and also makes it a potent cellular antioxidant. These activities serve as justification for its popular use as food supplement. Another quinone with similarities to the naturally occurring CoQ10 is idebenone, which shares its quinone moiety with CoQ10, but at the same time differs from CoQ10 by the presence of a much shorter, less lipophilic tail. However, despite its similarity to CoQ10, idebenone cannot be isolated from any natural sources but instead was synthesized and selected as a pharmacologically active compound in the 1980s by Takeda Pharmaceuticals purely based on its pharmacological properties. Several recent clinical trials demonstrated some therapeutic efficacy of idebenone in different indications and as a consequence, many practitioners question if the freely available CoQ10 could not be used instead. Here, we describe the molecular and pharmacological features of both molecules that arise from their structural differences to answer the question if idebenone is merely a CoQ10 analogue as frequently perpetuated in the literature or a pharmaceutical drug with entirely different features.

Topics: Adenosine Triphosphate; Antioxidants; Biological Products; Electron Transport; Humans; Membrane Potential, Mitochondrial; Mitochondria; Molecular Weight; NAD(P)H Dehydrogenase (Quinone); Structure-Activity Relationship; 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

Treatment of mitochondrial respiratory chain (MRC) disorders is extremely difficult, however, coenzyme Q10 (CoQ10) and its synthetic analogues are the only agents which have shown some therapeutic benefit to patients. CoQ10 serves as an electron carrier in the MRC as well as functioning as a potent lipid soluble antioxidant. CoQ10 supplementation is fundamental to the treatment of patients with primary defects in the CoQ10 biosynthetic pathway. The efficacy of CoQ10 and its analogues in the treatment of patients with MRC disorders not associated with a CoQ10 deficiency indicates their ability to restore electron flow in the MRC and/or increase mitochondrial antioxidant capacity may also be important contributory factors to their therapeutic potential.

Topics: Animals; Ataxia; Humans; Mitochondrial Diseases; Molecular Structure; Muscle Weakness; Treatment Outcome; Ubiquinone

Friedreich's ataxia is a debilitating progressive neurodegenerative disease associated with cardiomyopathy and other features. The underlying cause is a deficiency of the mitochondrial protein frataxin which causes mitochondrial iron deposition, increased oxidative stress and impaired adenosine triphosphate production. Over the last 15 years, multiple clinical trials have assessed the efficacy of antioxidant agents in this disease. This article reviews trials of the two most important agents, namely co-enzyme Q10 and idebenone.

Topics: Antioxidants; Friedreich Ataxia; Humans; Ubiquinone

Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinically-relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

Topics: Antioxidants; Arginine; Clinical Trials as Topic; Creatine; Exercise Therapy; Humans; Mitochondrial 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

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

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: Adolescent; Compassionate Use Trials; Female; Friedreich Ataxia; Humans; Insulin-Like Growth Factor I; Ubiquinone; Vitamin E

Topics: Animals; Inflammation; Mice; Mitochondria; Ubiquinone

Current peroxisome proliferator-activated receptor (PPAR)-targeted drugs, such as the PPARγ-directed diabetes drug rosiglitazone, are associated with undesirable side effects due to robust agonist activity in non-target tissues. To find new PPAR ligands with fewer toxic effects, we generated transgenic zebrafish that can be screened in high throughput for new tissue-selective PPAR partial agonists. A structural analog of coenzyme Q

Topics: 3T3-L1 Cells; Animals; Animals, Genetically Modified; Benzoquinones; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Ligands; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; PPAR alpha; PPAR gamma; Ubiquinone; Zebrafish

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

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)) and its analogs are used therapeutically by virtue of their functions as electron carriers, antioxidant compounds, or both. However, published studies suggest that different ubiquinone analogs may produce divergent effects on oxidative phosphorylation and oxidative stress.. To test these concepts, we have evaluated the effects of CoQ(10), coenzyme Q(2) (CoQ(2)), idebenone, and vitamin C on bioenergetics and oxidative stress in human skin fibroblasts with primary CoQ(10) deficiency. A final concentration of 5 microM of each compound was chosen to approximate the plasma concentration of CoQ(10) of patients treated with oral ubiquinone. CoQ(10) supplementation for one week but not for 24 hours doubled ATP levels and ATP/ADP ratio in CoQ(10) deficient fibroblasts therein normalizing the bioenergetics status of the cells. Other compounds did not affect cellular bioenergetics. In COQ2 mutant fibroblasts, increased superoxide anion production and oxidative stress-induced cell death were normalized by all supplements.. THESE RESULTS INDICATE THAT: 1) pharmacokinetics of CoQ(10) in reaching the mitochondrial respiratory chain is delayed; 2) short-tail ubiquinone analogs cannot replace CoQ(10) in the mitochondrial respiratory chain under conditions of CoQ(10) deficiency; and 3) oxidative stress and cell death can be counteracted by administration of lipophilic or hydrophilic antioxidants. The results of our in vitro experiments suggest that primary CoQ(10) deficiencies should be treated with CoQ(10) supplementation but not with short-tail ubiquinone analogs, such as idebenone or CoQ(2). Complementary administration of antioxidants with high bioavailability should be considered if oxidative stress is present.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Ascorbic Acid; Cells, Cultured; Fibroblasts; Humans; Molecular Structure; Superoxides; Ubiquinone

Effect of CoQ compounds (Qs) on reactive oxygen (ROS) generation by mitochondrial complex I was studied using rat liver mitochondria and chemiluminescence probe L012. Kinetic analysis revealed that short chain Qs, such as Q2 and idebenone enhanced ROS generation by mitochondrial NADH oxidase system by a succinate-inhibitable mechanism. Lipid peroxidation in mitochondrial membranes induced by NADH and iron was inhibited by short chain Qs. The inhibitory activity was enhanced by co-oxidation of succinate as determined by chemiluminescence method and by electron spin resonance spectroscopy. These results suggested that the reduced form of short chain Qs inhibited mitochondrial ROS generation and lipid peroxidation.

Topics: Animals; Male; Metabolic Networks and Pathways; Mitochondria, Liver; Oxidoreductases; Rats; Rats, Wistar; Reactive Oxygen Species; Ubiquinone

We studied plasma and cerebrospinal fluid (CSF) concentrations of idebenone in five Friedreich ataxia patients on treatment with this antioxidant, and plasma and CSF ubiquinone-10 (Q (10)) concentrations in 15 controls. CSF idebenone concentrations were below the detection limit in 3 Friedreich ataxia patients and no association could be demonstrated between plasma and CSF idebenone values. Q (10) CSF concentrations (median: 2.25 nmol/L) were approximately 300 times lower than those of plasma (median: 0.77 micro mol/L). No correlation was observed between plasma and CSF Q (10) concentrations. A significantly positive correlation was observed between CSF total protein values (range 8.1 - 107.5 mg/dL; median: 29.5) and CSF Q (10) concentrations (Spearman test: r = 0.664; p = 0.01). Our findings suggest that less idebenone is distributed to the brain than to other tissues, although CSF does not appear to be an appropriate material for treatment monitoring of idebenone and other quinoid compounds.

Topics: Adolescent; Adult; Antioxidants; Benzoquinones; Blood-Brain Barrier; Case-Control Studies; Child; Coenzymes; Friedreich Ataxia; Humans; Ubiquinone

Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi-systemic disease with loss of sensory neurons and life-threatening hypertrophic cardiomyopathy as its most severe manifestations. Reduced levels of the mitochondrial protein frataxin lead to cell-damaging oxidative stress and consequently FRDA is considered as a model for more common neurodegenerative disorders in which reactive radicals and oxidative stress are involved. We have developed a cellular assay system that discriminates between fibroblasts from FRDA patients and unaffected donors on the basis of their sensitivity to pharmacological inhibition of de novo synthesis of glutathione. With this assay we observed that supplementation with selenium effectively improved the viability of FRDA fibroblasts, indicating that basal selenium concentrations are not sufficient to allow an adequate increase in the activity of certain detoxification enzymes (such as GPX). Furthermore, we characterized potential drug candidates and found that idebenone, a mitochondrially localized antioxidant that ameliorates cardiomyopathy in FRDA patients, as well as other lipophilic antioxidants protected FRDA cells from cell death. Our results also demonstrate for the first time that small-molecule GPX mimetics have potential as a novel treatment strategy for Friedreich Ataxia and presumably also for other neurodegenerative diseases with mitochondrial impairment.

Topics: Benzoquinones; Biological Assay; Biomimetics; Coenzymes; Fibroblasts; Friedreich Ataxia; Glutathione; Glutathione Peroxidase; Humans; In Vitro Techniques; Models, Biological; Ubiquinone

Topics: Aconitate Hydratase; Benzoquinones; Coenzymes; Deferoxamine; Electron Transport Complex II; Friedreich Ataxia; Humans; Iron; Iron-Sulfur Proteins; Multienzyme Complexes; Oxidoreductases; Quinones; Succinate Dehydrogenase; Ubiquinone

A 16-year-old boy with mitochondrial encephalomyopathy had seizures, short stature, muscle weakness, progressive hearing loss, mental retardation, and myoclonus. His cranial computed tomography showed progressive calcification in the basal ganglia and cerebral atrophy. Muscle biopsy revealed many ragged-red fibers with variable cytochrome c oxidase activity and some strongly succinate dehydrogenase-reactive blood vessels. Sequence analysis of the entire mitochondrial DNA revealed a novel point mutation in the tRNA-Thr gene at nucleotide pair 15915. Serum lactate levels were decreased by high-dose coenzyme Q10 (CoQ10) therapy. The spectral power density, a parameter of background activity on electroencephalography, was markedly improved after additional administration of idebenone. After initiation of combined CoQ10 and idebenone therapy, the clinical abnormalities did not progress for 16 months.

Topics: Adolescent; Benzoquinones; Brain; Coenzymes; DNA, Mitochondrial; Electroencephalography; Humans; Male; Mitochondrial Encephalomyopathies; Neurologic Examination; Point Mutation; RNA, Transfer, Thr; Sequence Analysis; Ubiquinone

The ability of the benzoquinone coenzyme Q-10 or its derivative QSA-10 (idebenone) to protect against lipid peroxidation and protein damage mediated by the pro-oxidative system NADPH/ADP/Fe3+ was tested in a rat liver microsomal model incubated in University of Wisconsin (UW) or histidine-tryptophan-ketoglutarate (HTK) solutions. Lipid peroxidation, as followed by direct determination of lipid hydroperoxides and by monitoring of malondialdehyde equivalents, was 1.8-fold enhanced in HTK and 3-fold attenuated in UW compared with HEPES buffer. Function and integrity of microsomal enzymes were investigated using glutathione S-transferase and cytochrome P-450 IIIA activity as assessed by lidocaine N-deethylation to monoethylglycinexylidide as well as by Western blot analysis of the cytochrome P-450 IIIA protein. Glutathione S-transferase activity was reduced by about 70% in HEPES compared with 50% in HTK and 36% in UW. Cytochrome P-450 IIIA was inactivated by about 75% in HEPES and HTK, compared with 55% in UW. The enzyme inactivation was paralleled by a loss of immunoreactive cytochrome P-450 IIIA protein. Supplementation of HTK with 0.1 mumol/L QSA-10 offered complete protection against lipid peroxidation, compared with 100 mumol/L with Q-10. QSA-10 (20 mumol/L) prevented protein damage in both preservation solutions, whereas Q-10 (20 mumol/L) offered only partial protection in UW and had no effect in HTK. The use of QSA-10 during liver transplantation may therefore have the potential of increasing the efficacy of organ preservation, maintaining donor organ quality, and preventing reperfusion injury. It is suitable for human use and has energy-conserving properties in addition to its antioxidant nature.

Topics: Adenosine; Allopurinol; Animals; Antioxidants; Aryl Hydrocarbon Hydroxylases; Benzoquinones; Coenzymes; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Free Radicals; Glutathione; Insulin; Lipid Peroxidation; Male; Microsomes, Liver; Organ Preservation; Organ Preservation Solutions; Oxidoreductases, N-Demethylating; Raffinose; Rats; Rats, Wistar; Ubiquinone

A rise in blood and liver acetaldehyde concentrations following an intragastric administration of ethanol to rats was significantly inhibited when the quinone derivatives 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone (ubidecarenone, coenzyme Q10), 4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (pyrroloquinoline quinone, PQQ) and 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone) were injected intraperitoneally, prior to ethanol load, at a dose of 10, 11.5 and 30 mg/kg of body weight, respectively. When acetaldehyde was incubated in vitro with 1,4-benzoquinone (3.7-13.0 mM) or PQQ (1.4-4.9 mM) at 0 and 40 degrees C, the acetaldehyde concentrations slowly decreased with incubation time at 40 degrees C. The results suggest that low acetaldehyde concentrations following ethanol load are due to an accelerated oxidation of acetaldehyde by PQQ in the liver and the circulating blood.

Topics: Acetaldehyde; Animals; Benzoquinones; Coenzymes; Ethanol; In Vitro Techniques; Liver; Male; PQQ Cofactor; Quinolones; Quinones; Rats; Rats, Inbred Strains; Ubiquinone

Topics: Acidosis, Lactic; Benzoquinones; Brain Diseases, Metabolic; Coenzymes; Female; Humans; Middle Aged; Mitochondria, Muscle; Neuromuscular Diseases; Quinones; Syndrome; Ubiquinone

Lipid peroxidation in rat brain mitochondria was induced by NADH in the presence of ADP and FeCl3. CV-2619 inhibited the lipid peroxidation in a concentration-dependent manner; the concentration giving 50% inhibition (IC50) was 84 microM. In addition, the inhibitory effect of CV-2619 was strongly enhanced by adding substrates of mitochondrial respiration; when succinate, glutamate, or succinate plus glutamate was added, the IC50 of CV-2619 was changed to 1.1, 10, or 0.5 microM, respectively. Metabolites of CV-2619 also inhibited the lipid peroxidation. The inhibitory effect of CV-2619 on mitochondrial lipid peroxidation disappeared when TTFA, an inhibitor of complex II in mitochondrial respiratory chain, was added. The results indicate that in mitochondria CV-2619 is changed to its reduced form which inhibits lipid peroxidation.

Topics: Animals; Antimycin A; Benzoquinones; Brain; Coenzymes; gamma-Aminobutyric Acid; Lipid Peroxides; Male; Mitochondria; NAD; Oxygen Consumption; Pantothenic Acid; Quinones; Rats; Rats, Inbred Strains; Rotenone; Thenoyltrifluoroacetone; Ubiquinone; Vitamin E