Antioxidant Idebenone Research Articles

Idebenone protects the kidneys of rats with renovascular arterial hypertension by inhibiting oxidative stress and apoptosis.

Here, the protective effect of antioxidant Idebenone (IDB) on renovascular hypertension was studied. The two-kidney one-clip (2K-1C) model of renal hypertension was established. The rats were divided into 3 groups: sham-operation group, 2K-1C renal hypertensive rats' model group and model treated with IDB group. The mean arterial blood pressure (MBP) of rats was measured and pathological condition of kidney was observed by H&E staining. The change of renal damage biomarkers (Cre, BUN, urine proteins), inflammatory factors (IL-6, IL-1β and TNF-α), oxidative stress ratio and key factors (MDA, SOD and CAT) were assessed by kits. The apoptosis key proteins (BAD, BAX, Caspase9, GSK-3β) were detected via Western blot. The 2K-1C model of renal hypertension was established. IDB reduced the MBP, Cre, BUN, urine proteins and improved the pathological condition of 2K-1C kidney. IDB restrained the inflammation factors (IL-6, IL-1β and TNF-α) and oxidative stress in kidney of renal hypertensive rats' model. Besides, IDB suppressed the expression of apoptosis key factors (BAD, BAX, Caspase9, GSK-3β) in kidney of renal hypertensive rats' model. IDB protects the kidneys of rats with renovascular arterial hypertension by inhibiting inflammation, oxidative stress, and apoptosis. These findings might provide medication guidance for IDB in renovascular arterial hypertension.

Long-Acting Heterodimeric Paclitaxel-Idebenone Prodrug-Based Nanomedicine Promotes Functional Recovery after Spinal Cord Injury.

After spinal cord injury (SCI), successive systemic administration of microtubule-stabilizing agents has been shown to promote axon regeneration. However, this approach is limited by poor drug bioavailability, especially given the rapid restoration of the blood-spinal cord barrier. There is a pressing need for long-acting formulations of microtubule-stabilizing agents in treating SCI. Here, we conjugated the antioxidant idebenone with microtubule-stabilizing paclitaxel to create a heterodimeric paclitaxel-idebenone prodrug via an acid-activatable, self-immolative ketal linker and then fabricated it into chondroitin sulfate proteoglycan-binding nanomedicine, enabling drug retention within the spinal cord for at least 2 weeks and notable enhancement in hindlimb motor function and axon regeneration after a single intraspinal administration. Additional investigations uncovered that idebenone can suppress the activation of microglia and neuronal ferroptosis, thereby amplifying the therapeutic effect of paclitaxel. This prodrug-based nanomedicine simultaneously accomplishes neuroprotection and axon regeneration, offering a promising therapeutic strategy for SCI.

The Parkinson’s disease-associated mutation LRRK2 G2385R alters mitochondrial biogenesis via the PGC-1α-TFAM pathway

Mutations in the Leucine-rich repeat protein kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson’s disease (PD). Although LRRK2 has been extensively studied, the pathogenic mechanism of the LRRK2 G2385R mutation, which is most common in Asian populations, especially in the Chinese Han population, remains unclear. In this study, we demonstrated that the LRRK2 G2385R mutation in HEK293T cells led to a reduction in cellular PGC-1α protein expression and inhibition of mitochondrial biogenesis through the PGC-1α-TFAM pathway. This resulted in a decrease in mitochondrial genome expression, which in turn impaired the normal electron transfer process of the oxidative phosphorylation respiratory chain, leading to mitochondrial dysfunction and onset of apoptosis. The mitochondrial dysfunction and apoptosis caused by the LRRK2 G2385R mutation were significantly alleviated by antioxidant Idebenone, which provides a theoretical basis for the subsequent development of precise treatment specifically for PD patients with LRRK2 G2385R mutation. Further validation of our findings in neurons and animal models are necessary.

Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy.

Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial genetic disease that causes blindness in young adults. Over 50 inherited mitochondrial DNA (mtDNA) variations are associated with LHON; however, more than 95% of cases are caused by one of three missense variations (m.11778 G > A, m.3460 G > A, and m.14484 T > C) encoding for subunits ND4, ND1, and ND6 of the respiration complex I, respectively. These variants remain silent until further and currently poorly understood genetic and environmental factors precipitate the visual loss. The clinical course that ensues is variable, and a convincing treatment for LHON has yet to emerge. In 2015, an antioxidant idebenone (Raxone) received European marketing authorisation to treat visual impairment in patients with LHON, and since then it was introduced into clinical practice in several European countries. Alternative therapeutic strategies, including gene therapy and gene editing, antioxidant and neurotrophic agents, mitochondrial biogenesis, mitochondrial replacement, and stem cell therapies are being investigated in how effective they might be in altering the course of the disease. Allotopic gene therapies are in the most advanced stage of development (phase III clinical trials) whilst most other agents are in phase I or II trials or at pre-clinical stages. This manuscript discusses the phenotype and genotype of the LHON disease with complexities and peculiarities such as incomplete penetrance and gender bias, which have challenged the therapies in development emphasising the most recent use of gene therapy. Furthermore, we review the latest results of the three clinical trials based on adeno-associated viral (AAV) vector-mediated delivery of NADH dehydrogenase subunit 4 (ND4) with mitochondrial targeting sequence, highlighting the differences in the vector design and the rationale behind their use in the allotopic transfer.

Intergenerational effects of the antioxidant Idebenone on the placentas of rats with gestational diabetes mellitus

Experimental models of maternal diabetes lead to the intrauterine programming of Gestational Diabetes Mellitus (GDM) in the offspring, together with an intrauterine proinflammatory environment, feto-placental metabolic alterations and fetal overgrowth. The aim of this work was to evaluate the effect of the mitochondrial antioxidant Idebenone given to F0 mild pregestational diabetic rats on the development of GDM in their F1 offspring and the intergenerational programming of a pro-oxidant/proinflammatory environment that affects the placentas of F2 fetuses. Control and mild pregestational diabetic female rats (F0) were mated with control males, and Idebenone or vehicle was administered to diabetic rats from day 1 of gestation to term. The F1 female offspring were mated with control males and maternal and fetal plasma samples were obtained for metabolic determinations at term. The F2 fetuses and placentas were weighed, and placental protein levels and peroxynitrite-induced damage (immunohistochemistry), mRNA levels (PCR), nitric oxide production (Griess reaction), and number of apoptotic cells (TUNEL) were evaluated. The F1 offspring of F0 diabetic rats (treated or not with Idebenone) developed GDM. The placentas of GDM rats showed a decrease in the mRNA levels of manganese superoxide dismutase and an increase in the production of nitric oxide, peroxynitrite-induced damage, and connective tissue growth factor levels, alterations that were prevented by the maternal Idebenone treatment in F0 rats. In conclusion, the maternal treatment with Idebenone in pregestational diabetic F0 rats ameliorates the pro-oxidant/proinflammatory environment that affects the placentas of F2 fetuses, although it does not prevent F1 rats from developing GDM.

Thermo-Responsive PLGA-PEG-PLGA Hydrogels as Novel Injectable Platforms for Neuroprotective Combined Therapies in the Treatment of Retinal Degenerative Diseases.

The present study aims to develop a thermo-responsive-injectable hydrogel (HyG) based on PLGA-PEG-PLGA (PLGA = poly-(DL-lactic acid co-glycolic acid); PEG = polyethylene glycol) to deliver neuroprotective agents to the retina over time. Two PLGA-PEG PLGA copolymers with different PEG:LA:GA ratios (1:1.54:23.1 and 1:2.25:22.5) for HyG-1 and HyG-2 development respectively were synthetized and characterized by different techniques (gel permeation chromatography (GPC), nuclear magnetic resonance (NMR), dynamic light scattering (DLS), critical micelle concentration (CMC), gelation and rheological behaviour). According to the physicochemical characterization, HyG-1 was selected for further studies and loaded with anti-inflammatory drugs: dexamethasone (0.2%), and ketorolac (0.5%), alone or in combination with the antioxidants idebenone (1 µM) and D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) (0.002%). In vitro drug release and cytotoxicity studies were performed for the active substances and hydrogels (loaded and drug-free). A cellular model based on oxidative stress was optimized for anti-inflammatory and antioxidant screening of the formulations by using retinal-pigmented epithelial cell line hTERT (RPE-1). The copolymer 1, used to prepare thermo-responsive HyG-1, showed low polydispersity (PDI = 1.22) and a strong gel behaviour at 25% (w/v) in an isotonic buffer solution close to the vitreous temperature (31–34 °C). Sustained release of dexamethasone and ketorolac was achieved between 47 and 62 days, depending on the composition. HyG-1 was well tolerated (84.5 ± 3.2%) in retinal cells, with values near 100% when the anti-inflammatory and antioxidant agents were included. The combination of idebenone and dexamethasone promoted high oxidative protection in the cells exposed to H2O2, with viability values of 86.2 ± 14.7%. Ketorolac and dexamethasone-based formulations ameliorated the production of TNF-α, showing significant results (p ≤ 0.0001). The hydrogels developed in the present study entail a novel biodegradable tool to treat neurodegenerative processes of the retina overtime.

Expert recommendation: treatment of nonambulatory patients with Duchenne muscular dystrophy

HintergrundDie Muskeldystrophie Duchenne (DMD) ist die häufigste genetische neuromuskuläre Krankheit im Kindesalter, bei der es meist im Alter von 9 bis 11 Jahren zum Verlust der Gehfähigkeit kommt.Ziel der Arbeit und Material und MethodenAuf der Grundlage aktueller Leitlinien und Studien erarbeiteten neuropädiatrische und neurologische Experten im Rahmen eines von der Firma PTC Therapeutics GmbH (Frankfurt am Main, Deutschland), die die Substanz Ataluren vertreibt, gesponserten Advisory Boards Empfehlungen zur Behandlung nichtgehfähiger Patienten mit DMD mit Schwerpunkt medikamentöse Therapien von Erwachsenen.Ergebnisse und DiskussionDer Verlust der Gehfähigkeit wird in Studien sehr unterschiedlich definiert und bezieht sich u. a. auf die Rollstuhlpflicht, das selbständige Gehen ohne Hilfsmittel oder die maximale Gehstrecke. Grundlage der Therapie von Patienten mit DMD in jedem Krankheitsstadium sind supportive und symptomatische Maßnahmen, die in der Regel auch nach dem Verlust der Gehfähigkeit intensiv weitergeführt werden sollten. Zusätzlich stehen den Patienten medikamentöse Therapien mit dem Ziel der Modifikation des Krankheitsverlaufes zur Verfügung. Glukokortikoide bilden den Stützpfeiler der medikamentösen Therapie auch über den Verlust der Gehfähigkeit hinaus, dann meist in reduzierter Dosis. Für Patienten mit DMD aufgrund einer Nonsense-Mutation (nmDMD), ca. 13 % aller DMD-Patienten, steht Ataluren als potenziell dystrophinwiederherstellende, krankheitsmodifizierende Therapie zur Verfügung; klinische Daten aus dem STRIDE-Register zeigen eine verzögerte Krankheitsprogression auch nach Verlust der Gehfähigkeit. Zum Exon-Skipping liegen für erwachsene Patienten derzeit noch keine belastbaren Daten vor. Das Antioxidans Idebenon kommt bei nichtgehfähigen, jugendlichen Patienten ohne therapeutische Alternative, die nicht mit Glukokortikoiden behandelt werden können, infrage. Ataluren eignet sich zur kombinierten Behandlung mit Glukokortikoiden, eine Kombination von Idebenon und Glukokortikoiden wird derzeit in einer klinischen Studie überprüft. Eine Add-on-Therapie mit Idebenon zusätzlich zu Ataluren ist bei nichtgehfähigen nmDMD-Patienten zu erwägen. Bedingt durch die Tatsache, dass sich einige der diskutierten Therapieoptionen noch in der Phase der klinischen Prüfung befinden oder noch keine oder nur begrenzte Daten für ältere Patienten mit DMD vorliegen, handelt es sich um Expertenempfehlungen entsprechend der Evidenzklasse IV.

Therapeutic Options in Hereditary Optic Neuropathies.

Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber’s Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.

Pathophysiological features of chronic cerebrovascular diseases and possibilities of complex neuroprotective therapy

The article discusses the principles of neuroprotective therapy as a pathogenetically justified direction in chronic cerebrovascular diseases (CVD). The results of numerous clinical trials demonstrated efficacy, safety, a wide range of pharmacological effects and good tolerability of the powerful antioxidant Idebenone (Neyromet), as well as domestic cytoprotector, Choline alphosceratus of (Cerepro®), affecting the basic pathophysiological processes of the ischemic cascade at CVD. The role of rational multimodal pharmacotherapy of CVD, which provides the necessary energy for the processes of neuroprotection and neuroplasticity of brain cells, is emphasized.

Effect of the antioxidant idebenone on maternal diabetes-induced embryo alterations during early organogenesis

Can maternal treatments with idebenone, a structural analogue of coenzyme Q10, prevent alterations on markers of proinflammatory-prooxidant processes, on the expression of genes involved in mitochondrial biogenesis and function, and on the apoptotic rate in embryos from mild diabetic rats? A mild diabetic rat model was induced by neonatal-streptozotocin administration (90 mg/kg subcutaneously). Female diabetic rats and controls were mated with healthy males. From day 1 of pregnancy, control and diabetic rats were orally treated with idebenone (100 mg/kg daily). On day 10.5 of gestation, the embryos were explanted and prepared for immunohistochemical studies, for the evaluation of gene expression by reverse transcription polymerase chain reaction and for TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end-labelling assay analysis. Embryos from mild diabetic rats showed increased levels of nitrated proteins, 4-hydroxynonenal and matrix metalloproteinase 9, which were prevented by idebenone administration. We also found a decreased embryonic expression of cytochrome c oxidase and reduced mRNA levels of peroxisome proliferator activated receptor-γ coactivator-1-α and nuclear respiratory factor-1, both of which were prevented by idebenone administration to the diabetic pregnant rats. Embryos from mild diabetic rats also showed an increased apoptotic rate, which was diminished by idebenone treatment. Maternal idebenone treatment ameliorates altered parameters related to the prooxidant-proinflammatory environment found in embryos from mild diabetic rats, suggesting a putative treatment to prevent diabetes-induced embryo alterations.

The antioxidant idebenone fails to prevent or attenuate chronic experimental autoimmune encephalomyelitis in the mouse

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

Deferiprone and idebenone rescue frataxin depletion phenotypes in a Drosophila model of Friedreich's ataxia

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

Rapamycin reduces oxidative stress in frataxin-deficient yeast cells

Friedreich ataxia (FRDA) is a common form of ataxia caused by decreased expression of the mitochondrial protein frataxin. Oxidative damage of mitochondria is thought to play a key role in the pathogenesis of the disease. Therefore, a possible therapeutic strategy should be directed to an antioxidant protection against mitochondrial damage. Indeed, treatment of FRDA patients with the antioxidant idebenone has been shown to improve neurological functions. The yeast frataxin knock-out model of the disease shows mitochondrial iron accumulation, iron–sulfur cluster defects and high sensitivity to oxidative stress. By flow cytometry analysis we studied reactive oxygen species (ROS) production of yeast frataxin mutant cells treated with two antioxidants, N-acetyl-L-cysteine and a mitochondrially-targeted analog of vitamin E, confirming that mitochondria are the main site of ROS production in this model. Furthermore we found a significant reduction of ROS production and a decrease in the mitochondrial mass in mutant cells treated with rapamycin, an inhibitor of TOR kinases, most likely due to autophagy of damaged mitochondria.

Idebenone Induces Apoptotic Cell Death in the Human Dopaminergic Neuroblastoma SHSY-5Y Cells

Idebenone is a coenzyme Q10 analog and an antioxidant that has been used clinically to treat Friedreich Ataxia. Being an antioxidant, idebenone could have potential therapeutic potential to treat other neurodegenerative diseases such as Parkinson's disease in which oxidative stress plays a role in their pathogenesis. But whether idebenone can be used to treat Parkinson's disease has not been evaluated. In this study, we found that exposure of the dopaminergic neuroblastoma SHSY-5Y cells to 1-10μM idebenone for 72h had no effect on the cell viability revealed by trypan blue exclusion assay and MTT assay. However, cells exposed to 25μM or higher concentrations of idebenone showed extensive trypan blue-positive staining and significant reduction in cell viability revealed by MTT assay indicating that most of the cells were no longer viable. Idebenone-induced cell death was characterized by genomic DNA fragmentation and accumulation of cytochrome c in the cytosol indicating that the death was apoptotic in nature. In addition, idebenone induced an increase in the total RNA of the pro-apoptosis protein BAX, it also increased the caspase-3 activity in the cell lysates when compared with the untreated control cells or cells exposed to 10μM or lower concentrations of idebenone. The detrimental effect of idebenone was attenuated by glutathione, an antioxidant, suggesting that oxidative stress contributed to the idebenone-induced cell death. In conclusion, our results suggest that antioxidant idebenone induced apoptosis when used in high concentrations.

Antioxidant idebenone-loaded nanoparticles based on chitosan and N-carboxymethylchitosan

Nanoparticles based on chitosan (Ch) and N-carboxymethylchitosan ( N-CMCh) cross-linked with tripolyphosphate (TPP) were developed by co-drying with idebenone in different polymer-to-drug ratios (1.3:1 to 16:1) with 20% (wt/wt) colloidal silicon dioxide and tripolyphosphate (0.2 mg/mL). At high ratios (8:1 and 16:1) the spray-dried powder showed spherical and dense particles with a size close to 1 μm, allowing almost complete drug coating by the polymeric system and a high efficiency of drug incorporation (>90% and >80%, for Ch and N-CMCh, respectively). The nanoparticles showed a 10-fold increase of drug stability in comparison with free drug and preserved antioxidant activity in vitro. Compared with the severely irritative free form of idebenone, the nanoparticle formulation showed decreased mucous membrane irritation. These results revealed the potential of Ch and N-CMCh nanoparticles as carriers for a hydrophobic and irritative drug such as idebenone for topical or nasal use. From the Clinical Editor Chitosan and N-carboxymethylchitosan nanoparticles have potential roles as carriers for hydrophobic and irritative drugs such as the antioxidant idebenone for topical or nasal use.

Determination of the antioxidative capacity of an antioxidant complex and idebenone: an in vitro rapid and sensitive method

The goal of this study was to determine the ability of two putative antioxidant solutions to suppress the formation of superoxide anion radicals created by optical excitation of a photosensitizer and measured by highly sensitive luminometric detection. Solutions containing 3% antioxidant complex and 1% idebenone were tested. The antioxidant complex is an aqueous combination of botanical extracts rich in ferulic acid, caffeic acid, and other polyphenols. Idebenone is a lower molecular weight analog of coenzyme Q(10) (a potent antioxidant). Each was dissolved in lipid soluble reagents (solutions) and run through a Photochem (photochemiluminometer system) device. Their antioxidant capacity was expressed as nmol equivalents of synthetic vitamin E. Nine aliquots of each compound were measured. The mean antioxidant capacities for the 3% antioxidant complex and 1% idebenone were 525 +/- 23 and 213 +/- 14 nmol, respectively, with a statistically significant difference between the two compounds (P < 0.001). The 3% antioxidant solution possesses a significant antioxidative capacity, which was 2.5 times greater than the known antioxidant idebenone in a 1% solution as shown by the quenching of superoxide anion radicals measured by photochemiluminescence. This method provides rapid, accurate, and sensitive measurement of the antioxidant properties of lipid-soluble compounds.

Protection against Hydrogen Peroxide-Mediated Cytotoxicity in Friedreich's Ataxia Fibroblasts Using Novel Iron Chelators of the 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone Class

Iron-loading diseases remain an important problem because of the toxicity of iron-catalyzed redox reactions. Iron loading occurs in the mitochondria of Friedreich's ataxia (FA) patients and may play a role in its pathogenesis. This suggests that iron chelation therapy could be useful. We developed previously the lipophilic iron chelators known as the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) ligands and identified 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH) as the most promising analog. Hence, this study assessed the efficacy of PCTH and other PCIH analogs compared with various chelators, including deferiprone and desferrioxamine (DFO). Age- and sex-matched control and FA fibroblasts were preincubated with iron chelators and subsequently challenged with 50 microM H2O2 for up to 24 h. The current study demonstrates an interesting structure-activity relationship among the closely related PCIH series of ligands, with only PCTH being highly effective at preventing H2O2-induced cytotoxicity. PCTH increased FA fibroblast cell viability by up to 70%, whereas DFO rescued viability by 1 to 5% only. Hence, PCTH, which was well tolerated by cells was far more effective than DFO at preventing oxidative stress. It is noteworthy that kinetic studies demonstrated PCTH to rapidly penetrate cells to induce 59Fe efflux, whereas DFO, PCIH, 2-pyridylcarboxaldehyde benzoyl hydrazone, and 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone were far slower, indicating it is the rate of chelator permeation that is crucial for protection against H2O2. In addition, PCTH was found to be as effective as or more effective than conventional radical scavengers or the antioxidant idebenone (which has undergone clinical trials) at protecting cells against H2O2-mediated cytotoxicity. These findings further indicate the potential of PCTH for treatment of iron overload.

Effect of the Antioxidant Idebenone on Adverse Events Under Mycophenolate Mofetil Therapy in a Rat Model

Diarrhea and anemia are side effects of mycophenolic acid (MPA), but underlying mechanisms are not fully understood. Gene expression of major-alpha-hemoglobin and catalase was suppressed in livers of mycophenolate mofetil (MMF)-treated rats, suggesting MPA attenuates cellular defense against reactive oxygen species (ROS). We investigated whether the antioxidant idebenone might alleviate MPA-related side effects. Rats were treated as follows: group 1: controls; group 2: idebenone; group 3: MMF; and group 4: MMF/idebenone. Blood was collected weekly to determine cell counts, hemoglobin, MPA, plasma albumin, total protein, creatinine, and urea concentrations. On day 28 RNA was extracted from liver, kidneys, and bone marrow (BM). Colon and jejunum were examined histologically. High-dose MMF-treated rats developed diarrhea, dehydration, and weight loss. After a week, a significant decrease (P=0.001) in erythrocyte count and hemoglobin concentration was observed that was not influenced by idebenone. Degenerative changes in the jejunum were slightly attenuated by idebenone. Idebenone did not influence MPA-induced suppression of catalase. A significant suppression of major-alpha-hemoglobin and the erythropoietin (EPO)-receptor in BM of MMF-treated groups and almost complete absence of hemopoietic progenitor cells were observed. EPO-mRNA was markedly upregulated in the MMF-group and even more in the MMF/idebenone-group. Idebenone showed minimal benefit on MMF-related diarrhea and anemia. BM of MMF-treated rats revealed erythroid aplasia as a possible reason for anemia. Marked upregulation of EPO-mRNA presumably reflects a compensatory mechanism. Because ROS have the potential to suppress EPO expression, it can be hypothesized that enhanced EPO-mRNA expression in MMF/idebenone-treated rats is caused by antagonism of ROS.

Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial

Friedreich's ataxia (FA) is a progressive, multisystem, degenerative disorder caused by a reduction in frataxin. Loss of frataxin results in mitochondrial dysfunction and oxidative damage in patients and model systems. Previous studies have indicated that the antioxidant idebenone (5 mg/kg daily) reduces cardiac hypertrophy, but definite improvement in neurological function has not been shown. 48 genetically confirmed FA patients, aged 9-17 years, were enrolled in a 6-month, randomised, double-blind, placebo-controlled study. The patients received placebo or one of three doses of idebenone (approximately 5 mg/kg, 15 mg/kg, and 45 mg/kg), stratified by body weight. The primary endpoint was change from baseline in urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage. Secondary endpoints included changes in the international cooperative ataxia rating scale (ICARS), the FA rating scale (FARS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov, number NCT00229632. Idebenone was generally well tolerated with similar numbers of adverse events in each group. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved after discontinuation of treatment. 8OH2'dG concentrations were not increased, and did not significantly change with idebenone treatment. Whereas an overall analysis did not show a significant difference in ICARS, FARS, or ADL total scores, there were indications of a dose-dependent response in the ICARS score. A second, pre-specified analysis, excluding patients who required wheelchair assistance, showed a significant improvement in ICARS (Bonferroni p=0.03) and suggested a dose-related response in ICARS, FARS, and ADL scores. Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function.

Safety, Tolerability, and Pharmacokinetics of High-Dose Idebenone in Patients With Friedreich Ataxia

Friedreich ataxia (FA) is a progressive, multisystem degenerative disorder in which oxidative stress is believed to have a role. Recent clinical studies indicate that the antioxidant idebenone, administered at 5 mg/kg per day, reduces the cardiac hypertrophy that occurs in FA, but improvement in neurologic measures is unclear. Some studies suggest that higher doses of idebenone may be more effective, but pharmacology and toxicology at higher doses have not been investigated in human beings. To determine the safety, tolerability, and pharmacokinetics of increasing doses of idebenone in subjects with FA. Open-label, phase 1A dose-escalation trial followed by an open-label, 1-month phase 1B trial. National Institutes of Health Clinical Center, Bethesda, Md. Phase 1A included 78 subjects with FA (24 adults, 27 adolescents, and 27 children), and phase 1B included 15 subjects with FA (5 adults, 5 adolescents, and 5 children). Oral idebenone was administered to groups of 3 subjects in each age cohort during day 1. In phase 1A, the dose was increased in 10-mg/kg increments in each successive dose group to a maximum of 75 mg/kg. In phase 1B, oral idebenone was administered at 60 mg/kg divided in 3 doses per day for 1 month. We studied the type, number, and frequency of adverse events, and pharmacokinetic parameters including maximum drug concentration, time to maximum drug concentration, area under the curve, and half-life. In the first phase of the study, no dose-limiting toxicity was observed and the maximum allowed dose of 75 mg/kg was achieved in all cohorts. Plasma levels of total idebenone were found to increase proportional to drug dose up to 55 mg/kg. Variability in absorption of the drug was observed, but drug half-life was relatively consistent across dose levels. In the second phase of the study, 14 of 15 subjects with FA tolerated idebenone at a dose of 60 mg/kg per day for 1 month. All adverse events were mild, and pharmacokinetic parameters including maximum drug concentration, time to maximum drug concentration, and half-life did not differ significantly across age cohorts. These findings indicate that higher doses of idebenone lead to a proportional increase in plasma levels up to 55 mg/kg per day and that high-dose idebenone is well-tolerated in patients with FA. These findings are essential to planning efficacy trials of high-dose idebenone in FA and other degenerative diseases in which oxidative damage has been implicated.