coenzyme-q10 and Friedreich-Ataxia

Friedreich's Ataxia is an autosomal recessive genetic disease causing the defective gene product, frataxin. A body of literature has been focused on the attempts to counteract frataxin deficiency and the consequent iron imbalance, in order to mitigate the disease-associated pro-oxidant state and clinical course. The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane. A body of evidence points to the strong antioxidant properties of these cofactors, and to their potential contribution in mitoprotective strategies in Friedreich's Ataxia clinical evolution. Thus, we suggest the rationale for planning combination strategies based on the 3 mitochondrial cofactors and of some antioxidants and iron binders as mitoprotective cocktails in Friedreich Ataxia patients, calling attention to clinical practitioners of the importance to implement clinical trials.

Topics: Animals; Antioxidants; Carnitine; Deferiprone; Friedreich Ataxia; Humans; Iron Chelating Agents; Linoleic Acids; Mitochondria; 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

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

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

Coenzyme Q10 is administered for an ever-widening range of disorders, therefore it is timely to illustrate the latest findings with special emphasis on areas in which this therapeutic approach is completely new. These findings also give further insight into the biochemical mechanisms underlying clinical involvement of coenzyme Q10.. Cardiovascular properties of coenzyme Q10 have been further addressed, namely regarding myocardial protection during cardiac surgery, end-stage heart failure, pediatric cardiomyopathy and in cardiopulmonary resuscitation. The vascular aspects of coenzyme Q10 addressing the important field of endothelial function are briefly examined. The controversial issue of the statin/coenzyme Q10 relationship has been investigated in preliminary studies in which the two substances were administered simultaneously. Work on different neurological diseases, involving mitochondrial dysfunction and oxidative stress, highlights some of the neuroprotective mechanisms of coenzyme Q10. A 4-year follow-up on 10 Friedreich's Ataxia patients treated with coenzyme Q10 and vitamin E showed a substantial improvement in cardiac and skeletal muscle bioenergetics and heart function. Mitochondrial dysfunction likely plays a role in the pathophysiology of migraine as well as age-related macular degeneration and a therapy including coenzyme Q10 produced significant improvement. Finally, the effect of coenzyme Q10 was evaluated in the treatment of asthenozoospermia.. The latest findings highlight the beneficial role of coenzyme Q10 as coadjuvant in the treatment of syndromes, characterized by impaired mitochondrial bioenergetics and increased oxidative stress, which have a high social impact. Besides their clinical significance, these data give further insight into the biochemical mechanisms of coenzyme Q10 activity.

Topics: Antioxidants; Cardiovascular Diseases; Coenzymes; Friedreich Ataxia; Humans; Macular Degeneration; Migraine Disorders; Mitochondria; Oxidative Stress; Ubiquinone

Topics: Amyotrophic Lateral Sclerosis; Child; Clinical Trials as Topic; Coenzymes; Friedreich Ataxia; Heart Arrest; Humans; Huntington Disease; Mitochondrial Diseases; Nervous System Diseases; Parkinson Disease; Ubiquinone

Coenzyme Q10 (Q10) is available as an over-the-counter dietary supplement in the United States. While its use could be considered a form of alternative therapy, the medical profession has embraced the use of Q10 in specific disease states, including a series of neurologic and muscular diseases. Clinical laboratory monitoring is available for measurement of total Q10 in plasma and tissue and for measurement of redox status, ie, the ratio of reduced and oxidized forms of Q10. Many published studies have been anecdotal, in part owing to the rarity of some diseases involved. Unfortunately, many studies do not report Q10 levels, and, thus, the relationship of clinical response to Q10 concentration in plasma frequently is not discernible. Consistent laboratory monitoring of patients treated with this compound would help ease interpretation of the results of the treatment, especially because so many formulations of Q10 exist in the marketplace, each with its own bioavailability characteristics. Q10 has an enviable safety profile and, thus, is ideal to study as an adjunct to more conventional therapy. Defining patient subpopulations and characteristics that predict benefit from exogenous Q10 and defining therapeutic ranges for those particular applications are major challenges in this field.

Topics: Coenzymes; Epilepsies, Myoclonic; Friedreich Ataxia; Humans; Huntington Disease; Kearns-Sayre Syndrome; Mitochondrial Encephalomyopathies; Muscular Diseases; Nervous System Diseases; Parkinson Disease; Ubiquinone

Mitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis. These advances in our understanding of the disease mechanisms are enabling therapeutic avenues to be explored, in particular the use of established drugs such as antioxidants and enhancers of respiratory chain function. Vitamin E therapy has been shown to be beneficial in patients with ataxia with vitamin E deficiency, and CoQ10 therapy was effective in some patients with ataxia associated with CoQ10 deficiency. A combined therapy involving long term treatment with high doses of vitamin E and coenzyme Q10 has jointly targeted two of the major features of Friedreich's Ataxia; decreased mitochondrial respiratory chain function and increased oxidative stress. This therapy clearly showed a rapid and sustained increase in the energy generated by the FRDA heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation parallel those of the heart but to a lower level. While this therapy appeared to slow the predicted progression of some clinical symptoms a larger placebo controlled study is required to confirm these observations. Other antioxidant strategies have involved the use of Idebenone, selenium and N acetyl cysteine but only the use of Idebenone has involved structured trials with relatively large patient numbers. Idebenone clearly had an impact upon the cardiac hypertrophy in the majority of patients, although there have not been any other significant benefits reported to date.

Topics: Antioxidants; Coenzymes; Electron Transport; Frataxin; Friedreich Ataxia; Humans; Iron; Iron Chelating Agents; Iron-Binding Proteins; Mitochondria; Oxidative Stress; Ubiquinone

Friedreich's ataxia (FRDA), the most common inherited ataxia, is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein, which is severely reduced in FRDA patients. The demonstration that deficit of frataxin in FRDA is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of cardiac and skeletal muscle tissue energy metabolism, has established FRDA as a "new" nuclear encoded mitochondrial disease. Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q10 plus Vitamin E administration in this condition and provide a strong rationale for designing larger randomized clinical trials.

Topics: Antioxidants; Carrier Proteins; Coenzymes; Cytoprotection; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Stress; Point Mutation; Trinucleotide Repeats; Ubiquinone; Vitamin E

A pilot study of high dose coenzyme Q(10) (CoQ(10))/vitamin E therapy in Friedreich's ataxia (FRDA) patients resulted in significant clinical improvements in most patients. This study investigated the potential for this treatment to modify clinical progression in FRDA in a randomized double blind trial.. Fifty FRDA patients were randomly divided into high or low dose CoQ(10)/ vitamin E groups. The change in International Co-operative Ataxia Ratings Scale (ICARS) was assessed over 2 years as the primary end-point. A post hoc analysis was made using cross-sectional data.. At baseline serum CoQ(10) and vitamin E levels were significantly decreased in the FRDA patients (P < 0.001). During the trial CoQ(10) and vitamin E levels significantly increased in both groups (P < 0.01). The primary and secondary end-points were not significantly different between the therapy groups. When compared to cross-sectional data 49% of all patients demonstrated improved ICARS scores. This responder group had significantly lower baseline serum CoQ(10) levels.. A high proportion of FRDA patients have a decreased serum CoQ(10) level which was the best predictor of a positive clinical response to CoQ(10)/vitamin E therapy. Low and high dose CoQ(10)/vitamin E therapies were equally effective in improving ICARS scores.

Topics: Adolescent; Adult; Antioxidants; Dose-Response Relationship, Drug; Electron Transport Chain Complex Proteins; Endpoint Determination; Energy Metabolism; Female; Friedreich Ataxia; Humans; Male; Mitochondria; Muscle, Striated; Oxidative Stress; Predictive Value of Tests; Treatment Outcome; Ubiquinone; Up-Regulation; Vitamin E; Vitamin E Deficiency; Young Adult

Decreased mitochondrial respiratory chain function and increased oxidative stress have been implicated in the pathogenesis of Friedreich ataxia (FRDA), raising the possibility that energy enhancement and antioxidant therapies may be an effective treatment.. To evaluate the long-term efficacy of a combined antioxidant and mitochondrial enhancement therapy on the bioenergetics and clinical course of FRDA.. Open-labeled pilot trial over 47 months.Patients Seventy-seven patients with clinical and genetically defined FRDA. Intervention A combined coenzyme Q(10) (400 mg/d) and vitamin E (2100 IU/d) therapy of 10 patients with FRDA over 47 months.. Clinical assessment using echocardiography and the International Cooperative Ataxia Rating Scale and cardiac and skeletal muscle bioenergetics as assessed using phosphorus P 31 magnetic resonance spectroscopy.. There was a significant improvement in cardiac and skeletal muscle bioenergetics that was maintained throughout the 47 months of therapy. Echocardiographic data revealed significantly increased fractional shortening at the 35- and 47-month time points. Comparison with cross-sectional data from 77 patients with FRDA indicated the changes in total International Cooperative Ataxia Rating Scale and kinetic scores over the trial period were better than predicted for 7 patients, but the posture and gait and hand dexterity scores progressed as predicted.. This therapy resulted in sustained improvement in mitochondrial energy synthesis that was associated with a slowing of the progression of certain clinical features and a significant improvement in cardiac function.

Topics: Adolescent; Adult; Antioxidants; Child; Coenzymes; Drug Therapy, Combination; Energy Metabolism; Follow-Up Studies; Frataxin; Friedreich Ataxia; Heart; Humans; Iron-Binding Proteins; Middle Aged; Mitochondria; Muscle, Skeletal; Myocardium; Oxidative Stress; Pilot Projects; Treatment Outcome; Ubiquinone; Vitamin E

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

We report on the synthesis, biological and pharmacological activity of the tocoquinone natural product, α-tocopherol quinone (ATQ); an oxidative metabolite of α-tocopherol. ATQ is a potent cellular protectant against oxidative stress, whose biological activity is dependent upon its ability to undergo reversible two-electron redox cycling. ATQ is orally bioavailable, with a favorable pharmacokinetic profile and has demonstrated a beneficial clinical response in patients with Friedreich's ataxia. ATQ is a member of a broader class of vitamin E derived quinone metabolites which may be ascribable in whole or in part to the activity of vitamin E.

Topics: alpha-Tocopherol; Animals; CHO Cells; Cricetinae; Dogs; Dose-Response Relationship, Drug; Drug Design; Fibroblasts; Friedreich Ataxia; Humans; Hydrolases; Mice; Micronucleus Tests; Models, Chemical; NAD(P)H Dehydrogenase (Quinone); Nutritional Sciences; Oxidation-Reduction; Oxidative Stress; Quinones; Rats; Vitamin E

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