Idebenone Treatment Research Articles

Effects of idebenone on cognitive function and serum biomarkers in patients with amnestic mild cognitive impairment

ObjectivesThis retrospective study aimed to investigate the effects of idebenone on cognitive function and serum levels of superoxide dismutase (SOD) and high-sensitivity C-reactive protein (hs-CRP) in individuals with amnestic mild cognitive impairment (aMCI).MethodsRetrospective data were collected from the Neurology outpatient department of Liaocheng People’s Hospital from January 2021 to June 2023. Patients with a newly diagnosed aMCI who received treatment were included in the idebenone treatment group. The treatment group took 30 mg of oral idebenone three times a day for 6 months. A control group of 51 MCI patients who did not receive cholinesterase inhibitors or other cognitive-enhancing drugs during the period was selected. Cognitive function assessments and serum Biomarkers were conducted before and after treatment in both groups.ResultsMoCA scores were significantly improved after 6 months of idebenone treatment, and the difference was statistically significant. The delayed recall score was significantly improved, and the difference was statistically significant; The level of SOD increased and the level of high-sensitivity C-reactive protein decreased after the treatment, but there was no significant change in the control group.ConclusionsThe results of this study demonstrate that idebenone treatment significantly improves cognitive function in individuals with aMCI, particularly in the domain of delayed memory. In addition, idebenone reduces the degree of inflammation and oxidative stress and improves antioxidant levels. These findings suggest that idebenone may be a promising intervention for the management of cognitive impairments associated with aMCI.Graphical

Hereditary Optic Neuropathies

Hereditary optic neuropathies are a rare disease group, and Leber's Hereditary Optic Neuropathy (LHON), Dominant Optic Atrophy (DOA) and Recessive Optic Atrophies are included in this disease group. These diseases may be isolated or accompanied by other systemic disorders. Leber's Hereditary Optic Neuropathy is the most common hereditary mitochondrial disease. Leber's Hereditary Optic neuropathy presents with acute-subacute, painless vision loss in the 2nd-3rd decade of life, and the other eye is usually affected within 6-8 weeks. Dominant Optic Atrophy is the most common hereditary optic neuropathy and causes slowly progressive, bilateral, symmetric vision loss in the first decade. Recessive optic atrophy begins at an earlier age than DOA, and nystagmus and severe vision loss are observed in these patients. Although there is no definitive treatment for hereditary optic neuropathies today, idebenone treatment and gene therapy for 11778 gene mutation are performed for LHON.

Genetic variants of NQO1 affect the expression and activity of the protein, which determines the efficacy of idebenone treatment in Leber's hereditary optic neuropathy

Genetic variants of NQO1 affect the expression and activity of the protein, which determines the efficacy of idebenone treatment in Leber's hereditary optic neuropathy

Effects of idebenone and coenzyme Q10 on NLRP3/caspase-1/IL-1β pathway regulation on ethanol-induced hepatotoxicity in rats

Chronic and excessive alcohol consumption leads to liver toxicity. There is a need to investigate effective therapeutic strategies to alleviate alcohol-induced liver injury, which remains the leading cause of liver-related morbidity and mortality worldwide. Therefore here, we looked into and evaluated how ethanol-induced hepatotoxicity was affected by coenzyme Q10 (CoQ10) and its analog, idebenone (IDE), on the NLRP3/caspase-1/IL-1 pathway. Hepatotoxicity induced in rats through the oral administration of gradually increasing dosages of ethanol (from 2 to 6 g/kg/day) over 30 days and the effect of CoQ10 (10 or 20 mg/kg) and IDE (50 or 100 mg/kg) were evaluated. Serum hepatotoxicity markers (ALT, AST, GGT, ALP, and TBIL), tissue oxidative stress markers and the mRNA expressions of IL-1β, IL-18, TGF-β, NF-κB, NLRP3, and caspase-1 were evaluated. Masson’s trichrome staining was also used to visualize fibrosis in the liver tissue. The results indicated that ethanol exposure led to hepatotoxicity as well as considerable NLRP3/caspase-1/IL-1β pathway activation. Moreover, CoQ10 or IDE treatment reduced measured parameters in a dosage-dependent manner. Thus, by inhibiting the NLRP3/caspase-1/IL-1 pathway, CoQ10 and IDE can prevent the hepatotoxicity caused by ethanol, although CoQ10 is more effective than IDE. This study will provide insight into new therapeutic avenues that take advantage of the anti-inflammatory and antioxidant properties of CoQ10 and IDE in ethanol-induced liver diseases.

Idebenone ameliorates statin-induced myotoxicity in atherosclerotic ApoE−/− mice by reducing oxidative stress and improving mitochondrial function

Statins are the first line of choice for the treatment for atherosclerosis, but their use can cause myotoxicity, a common side effect that may require dosage reduction or discontinuation. The exact mechanism of statin-induced myotoxicity is unknown. Previous research has demonstrated that the combination of idebenone and statin yielded superior anti-atherosclerotic outcomes. Here, we investigated the mechanism of statin-induced myotoxicity in atherosclerotic ApoE−/− mice and whether idebenone could counteract it. After administering simvastatin to ApoE−/− mice, we observed a reduction in plaque formation as well as a decrease in their exercise capacity. We observed elevated levels of lactic acid and creatine kinase, along with a reduction in the cross-sectional area of muscle fibers, an increased presence of ragged red fibers, heightened mitochondrial crista lysis, impaired mitochondrial complex activity, and decreased levels of CoQ9 and CoQ10. Two-photon fluorescence imaging revealed elevated H2O2 levels in the quadriceps, indicating increased oxidative stress. Proteomic analysis indicated that simvastatin inhibited the tricarboxylic acid cycle. Idebenone treatment not only further reduced plaque formation but also ameliorated the impaired exercise capacity caused by simvastatin. Our study represents the inaugural comprehensive investigation into the mechanisms underlying statin-induced myotoxicity. We have demonstrated that statins inhibit CoQ synthesis, impair mitochondrial complex functionality, and elevate oxidative stress, ultimately resulting in myotoxic effects. Furthermore, our research marks the pioneering identification of idebenone's capability to mitigate statin-induced myotoxicity by attenuating oxidative stress, thereby safeguarding mitochondrial complex functionality. The synergistic use of idebenone and statin not only enhances the effectiveness against atherosclerosis but also mitigates statin-induced myotoxicity.

LEDT and Idebenone treatment modulate autophagy and improve regenerative capacity in the dystrophic muscle through an AMPK-pathway.

Considering the difficulties and challenges in Duchenne muscular dystrophy (DMD) treatment, such as the adverse effects of glucocorticoids, which are the main medical prescription used by dystrophic patients, new treatment concepts for dystrophic therapy are very necessary. Thus, in this study, we explore the effects of photobiomodulation (PBM; a non-invasive therapy) and Idebenone (IDE) treatment (a potent antioxidant), applied alone or in association, in dystrophic muscle cells and the quadriceps muscle, with special focus on autophagy and regenerative pathways. For the in vitro studies, the dystrophic primary muscle cells received 0.5J LEDT and 0.06μM IDE; and for the in vivo studies, the dystrophic quadriceps muscle received 3J LEDT and the mdx mice were treated with 200mg/kg IDE. LEDT and IDE treatment modulate autophagy by increasing autophagy markers (SQSTM1/p62, Beclin and Parkin) and signaling pathways (AMPK and TGF-β). Concomitantly, the treatments prevented muscle degeneration by reducing the number of IgG-positive fibers and the fibers with a central nucleus; decreasing the fibrotic area; up-regulating the myogenin and MCH-slow levels; and down-regulating the MyoD and MHC-fast levels. These results suggest that LEDT and IDE treatments enhance autophagy and prevented muscle degeneration in the dystrophic muscle of the experimental model. These findings illustrate the potential efficacy of LEDT and IDE treatment as an alternative therapy focused on muscle recovery in the dystrophic patient.

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900mg/day) in patients with LHON up to 5 years after symptom onset (N= 199) and over a treatment period of 24months, compared to an external natural history control cohort (N= 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.

Anti-Inflammatory Effects of Idebenone Attenuate LPS-Induced Systemic Inflammatory Diseases by Suppressing NF-κB Activation.

Inflammation is a natural protective process through which the immune system responds to injury, infection, or irritation. However, hyperinflammation or long-term inflammatory responses can cause various inflammatory diseases. Although idebenone was initially developed for the treatment of cognitive impairment and dementia, it is currently used to treat various diseases. However, its anti-inflammatory effects and regulatory functions in inflammatory diseases are yet to be elucidated. Therefore, this study aimed to investigate the anti-inflammatory effects of idebenone in cecal ligation puncture-induced sepsis and lipopolysaccharide-induced systemic inflammation. Murine models of cecal ligation puncture-induced sepsis and lipopolysaccharide-induced systemic inflammation were generated, followed by treatment with various concentrations of idebenone. Additionally, lipopolysaccharide-stimulated macrophages were treated with idebenone to elucidate its anti-inflammatory effects at the cellular level. Idebenone treatment significantly improved survival rate, protected against tissue damage, and decreased the expression of inflammatory enzymes and cytokines in mice models of sepsis and systemic inflammation. Additionally, idebenone treatment suppressed inflammatory responses in macrophages, inhibited the NF-κB signaling pathway, reduced reactive oxygen species and lipid peroxidation, and normalized the activities of antioxidant enzyme. Idebenone possesses potential therapeutic application as a novel anti-inflammatory agent in systemic inflammatory diseases and sepsis.

Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy

Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous. This hampers idebenone reduction. In its oxidized form, idebenone inhibits complex I, decreasing respiratory function in cells. By retrospectively analyzing a large cohort of idebenone-treated LHON patients, classified by their response totherapy, we show that patients with homozygous or compound heterozygous NQO1 variants have the poorest therapy response, particularly if carrying the m.3460G>A/MT-ND1 LHON mutation. These results suggest consideration of patient NQO1 genotype and mitochondrial DNA mutation in the context of idebenone therapy.

The temporal progression of retinal degeneration and early-stage idebenone treatment in the Pde6brd1/rd1 mouse model of retinal dystrophy

Photoreceptor cell death, primarily through apoptosis, related to retinal disorders like retinitis pigmentosa (RP), would result in vision loss. The pathological processes and crucial mutant conditions preceding photoreceptor cell demise are not well understood. This study aims to conduct an in-depth examination of early-stage changes in the widely utilized Pde6brd1/rd1 (rd1) mouse model, which has Pde6b gene mutations representing autosomal recessive RP disorder. We investigated the morphology and ultrastructure of retinal cells, including second-order neurons, during the initial phase of disease progression. Our findings revealed that mitochondrial alterations in rod photoreceptors were present as a predeath mutant state as early as postnatal day 3 (P3). The bipolar and horizontal cells from the rd1 mouse retina exhibited significant morphological changes in response to loss of photoreceptor cells, indicating that second-order neurons rely on these cells for their structures. Subsequent oral administration of idebenone, a mitochondria-protective agent, enhanced retinal function and promoted both photoreceptor cell survival and inner retinal second-order synaptogenesis in rd1 mice at P14. Our findings offer a mechanistic framework, suggesting that mitochondrial damage acts as an early driver for photoreceptor cell death in retinal degeneration.

Long‐term efficacy of idebenone in patients with Leber hereditary optic neuropathy in the LEROS study: Analysing change in visual acuity according to causative mutation and disease phase

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in severe vision loss. The causative mitochondrial DNA (mtDNA) mutation impacts disease progression and prognosis. In LEROS, a Phase IV, open‐label interventional study (Clinicaltrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of an external Natural History (NH) cohort. Here, we compare VA change from baseline to Month 24 according to primary mtDNA mutation and disease stage.Methods: Eyes of patients with LHON and either a m.G11778A, m.T14484C or m.G3460A, mtDNA mutation were stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 but ≤5 years). Data from 181 patients were compared to retrospective data from the NH cohort (N = 372), matched by time since symptom onset at baseline. We compare the difference in least squares‐mean VA change, or delta VA, from baseline to Month 24 in IDE versus NH eyes (a negative value favours IDE).Results: In treated subacute/dynamic m.G11778A eyes (n = 60 IDE), delta VA was −0.32 logMAR (p = 0.002) versus the NH cohort (n = 47). In chronic m.G11778A eyes, delta VA was −0.11 logMAR (n = 82 IDE vs n = 51 NH; p = 0.043). In subacute/dynamic m.T14484C eyes, delta VA was +0.20 logMAR (n = 35 IDE vs n = 10 NH; p = 0.285). In chronic m.T14484C eyes, delta VA was −0.52 logMAR (n = 11 IDE vs n = 18 NH; p < 0.001). In subacute/dynamic m.G3460A eyes, delta VA was +0.53 logMAR (n = 26 IDE vs n = 18 NH; p = 0.001). In chronic m.G3460A eyes, delta VA was −0.13 logMAR (n = 23 IDE vs n = 24 NH; p = 0.162).Conclusions: Idebenone improved VA in a large proportion of eyes; this benefit manifested to varying degrees depending on disease stage and mtDNA mutation. m.G11778A eyes saw a consistent benefit regardless of disease stage. m.T14484C and m.G3460A results should be interpreted with caution in some cases due to the relatively low number of eyes; further study is warranted.

Long‐term efficacy of idebenone in patients with Leber hereditary optic neuropathy in the LEROS study: Analysing change in visual acuity over time according to age at symptom onset

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to progressive, bilateral vision loss. Childhood‐onset LHON has a relatively good prognosis, suggesting that age at onset influences disease progression and potential response to treatment. In LEROS, a Phase IV, open‐label interventional study (ClinicalTrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of a Natural History (NH) cohort.Methods: LEROS included patients aged ≥12 years with a disease onset ≤5 years prior. Data from 181 patients were compared to retrospective data from a NH cohort (N = 372), matched by time since symptom onset. Here, we compare the difference in least squares‐mean VA change, or delta VA, from baseline to Month 24 in treated eyes versus those in the NH cohort (a negative value favours IDE). Eyes were stratified by time since symptom onset at baseline: subacute/dynamic (≤1 year) and chronic (>1 year) phase, and by age at symptom onset (<18 years, ≥18 years).Results: In treated subacute/dynamic eyes from the <18 years group (n = 22 IDE), delta VA was +0.38 logMAR (p = 0.020) relative to the NH cohort (n = 22). In the chronic phase, delta VA was −0.08 logMAR (n = 16 IDE vs n = 37 NH eyes; p = 0.405). In subacute/dynamic eyes from the ≥18 years group, delta VA was −0.18 logMAR (n = 99 IDE vs n = 53 NH; p = 0.060). In the chronic phase, delta VA was −0.21 logMAR (n = 100 IDE vs n = 56 NH; p < 0.001).Conclusions: In eyes of patients ≥18 years at symptom onset, VA improvement at Month 24 was greater in idebenone‐treated versus untreated NH eyes. Treatment benefit was particularly apparent in the chronic phase, corresponding to >10 additional letters on the ETDRS chart. In subacute/dynamic eyes, spontaneous VA recovery was unexpectedly high in the NH cohort. In chronic eyes from patients <18 years, a non‐significant trend favouring idebenone was observed.

Long‐term efficacy of idebenone in patients with Leber hereditary optic neuropathy according to age at symptom onset and disease phase: Results from the LEROS study

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in bilateral vision loss. Childhood‐onset LHON has a relatively good prognosis, suggesting that age influences disease progression and, potentially, treatment response. In LEROS, a Phase IV, open‐label interventional study (Clinicaltrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of an external Natural History (NH) cohort.Methods: LEROS included patients aged ≥12 years with a disease onset ≤5 years prior. Data from 181 patients were compared to retrospective data from a NH cohort (N = 372), matched by time since symptom onset. Here, we compare clinically relevant recovery (CRR) and clinically relevant worsening (CRW) from baseline to Month 24 in IDE eyes versus NH eyes, stratified by time since symptom onset at baseline: subacute/dynamic (≤1 year) and chronic (>1 year) phase, and by age at symptom onset (<18 years, ≥18 years).Results: In patients aged <18 years, VA outcomes were observed, in IDE versus NH eyes, as follows: CRR: subacute/dynamic 31.8% (7/22) vs 59.1% (13/22), p = 0.048; chronic 31.3% (5/16) vs 21.6% (8/37), p = 0.241; CRW: subacute/dynamic 26.3% (5/19) vs 21.4% (3/14), p = 0.558; chronic 8.3% (1/12) vs 19.2% (5/26), p = 0.078. In patients aged ≥18 years, the following VA outcomes were observed: CRR: subacute/dynamic 51.5% (51/99) vs 22.6% (12/53), p = 0.001; chronic 32.0% (32/100) vs 12.5% (7/56), p < 0.001; CRW: subacute/dynamic 25.7% (19/74) vs 62.9% (22/35), p < 0.001; chronic 1.8% (1/56) vs 20.6% (7/34), p = 0.003.Conclusions: Idebenone improved the ratio of positive to negative VA outcomes. Treatment benefit was particularly pronounced in patients ≥18 years at onset, with only non‐significant positive trends observed in chronic patients <18 years. Results in subacute/dynamic patients aged <18 years were limited by an unusually high recovery rate in the NH cohort, warranting further study.

Long‐term response to idebenone treatment in a patient with advanced Leber hereditary optic neuropathy

Aims/Purpose: To present a case with advanced LHON and its response to 2‐year‐treatment with idebenone, which was prescribed 13 years after the onset of the disease.Methods: A 40‐year‐old Caucasian male patient with a history of bilateral painless visual loss since the age of 28 was examined at our Ophthalmology department. His brother had also suffered similar visual loss. At presentation ETDRS best corrected visual acuity (BCVA) was counting fingers (CF) in both eyes (BE). Fundoscopy revealed pale optic discs bilaterally. Visual fields (30‐2) showed central scotomas in BE. During OCT/OCTA imaging of the optic disc RNFL and GCC thickness were decreased bilaterally. In electrophysiological assessment with flash visual evoked potentials a reduction in amplitude was recorded in BE but with normal latency. Full‐field ERG was within normal limits in BE. At the genetic test, a mitochondrial point mutation m. 3460 G>A at MT‐ND1 gene was detected, which was compatible with LHON. The patient was prescribed 300 mg idebenone per os three times/day for 24 months. Follow‐up visits were scheduled at 6, 12, 18 and 24 months.Results: At 6‐ and 12‐month follow‐up visits visual acuity, fundoscopic findings and OCT‐RNFL imaging remained unchanged. However, the patient reported subjective visual improvement bilaterally, with greater improvement in the visual field of the left eye. At 18 months following initiation of treatment an improvement of the visual field was documented in BE. No change of the GCC thickness was noted. At 2‐year follow‐up his condition remained improved.Conclusions: Delayed treatment with idebenone in advanced LHON can lead to subjective visual improvement. Moreover, an improvement in visual fields can also be documented even after 18 to 24 months of the initiation of the treatment.

Leber's Hereditary Optic Neuropathy (LHON): Clinical Experience and Outcomes after Long-Term Idebenone Treatment.

Leber's hereditary optic neuropathy (LHON) is a rare disease. Large studies are difficult to conduct; therefore, case reports provide valuable data. Since 2015, patients have been treated with Idebenone. The aim of this paper is to share our experience with diagnosing and managing patients in different stages of LHON. We designed a case series study, including four patients undergoing genetic testing and ophthalmologic examination. Criteria for Idebenone administration and follow-up were presented. All patients had mutation 11778G>A in MT-ND4. The first patient, an 82-year-old man, with long history of vision loss, had no indication for Idebenone. Two additional cases emerged within the same family: a 40-year-old brother and a 31-year-old sister. Both received Idebenone, with good outcomes only for the female. After a one-year regimen, they were lost to follow-up. The fourth patient, a 46-year-old man, was diagnosed in the subacute stage. Idebenone administration was deferred, allowing progression of visual field defects. After 17 months of treatment, visual improvement appeared. The treatment was continued for 36 months, with short interruptions, resulting in good outcomes. Our study demonstrated positive results with long-term Idebenone use. Contrary to medical literature, our female patient had a favorable evolution, despite the delayed diagnosis.

Idebenone Treatment in Patients with OPA1-Dominant Optic Atrophy: A Prospective Phase 2 Trial

ABSTRACT The aim of this study was to evaluate the therapeutic effect of idebenone in patients with OPA1-dominant optic atrophy (DOA). Sixteen patients with genetically confirmed OPA1-DOA were treated with 900 mg idebenone daily for 12 months. The primary endpoint was the best recovery/least deterioration of visual acuity. Secondary endpoints were the changes of visual acuity, colour vision, contrast sensitivity, visual field, peripapillary retinal nerve fibre layer thickness (pRNFLT), and visual-related quality of life. For the primary endpoint, a significant increase was observed for the right eye (p = .0027), for the left eye (p = .0111) and for the better-seeing eye (p = .0152). For visual fields, a significant improvement was observed for the left eye between baseline and 9 months (p = .0038). Regarding pRNFLT, a significant decrease was found for the left eye between baseline and 3 months (p = .0413) and between baseline and 6 months (p = .0448). In the visual function questionnaire, a significant improvement was observed in the subscale general vision (p = .0156) and in the composite score (p = .0256). In conclusion, best recovery of visual acuity improved, even though the amount of improvement was small. Furthermore, a maintenance of visual function after 12 months of idebenone intake could be observed as well as a significant improvement in vision-related quality of life.Whether this effect is due to idebenone treatment, the placebo effect, or is explainable by the natural progression of DOA, remains unclear. Trial registration: EU Clinical Trials Register, EudraCT Number: 2019-001493-28

LED therapy plus idebenone treatment targeting calcium and mitochondrial signaling pathways in dystrophic muscle cells.

Intracellular calcium dysregulation, oxidative stress, and mitochondrial dysfunction are some of the main pathway contributors towards disease progression in Duchenne muscular dystrophy (DMD). This study is aimed at investigating the effects of light emitting diode therapy (LEDT) and idebenone antioxidant treatment, applied alone or together in dystrophic primary muscle cells from mdx mice, the experimental model of DMD. Mdx primary muscle cells were submitted to LEDT and idebenone treatment and evaluated for cytotoxic effects and calcium and mitochondrial signaling pathways. LEDT and idebenone treatment showed no cytotoxic effects on the dystrophic muscle cells. Regarding the calcium pathways, after LEDT and idebenone treatment, a significant reduction in intracellular calcium content, calpain-1, calsequestrin, and sarcolipin levels, was observed. In addition, a significant reduction in oxidative stress level markers, such as H2O2, and 4-HNE levels, was observed. Regarding mitochondrial signaling pathways, a significant increase in oxidative capacity (by OCR and OXPHOS levels) was observed. In addition, the PGC-1α, SIRT-1, and PPARδ levels were significantly higher in the LEDT plus idebenone treated-dystrophic muscle cells. Together, the findings suggest that LEDT and idebenone treatment, alone or in conjunction, can modulate the calcium and mitochondrial signaling pathways, such as SLN, SERCA 1, and PGC-1α, contributing towards the improvement of the dystrophic phenotype in mdx muscle cells. In addition, data from the LEDT plus idebenone treatment showed slightly better results than those of each separate treatment in terms of SLN, OXPHOS, and SIRT-1.

Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber's Hereditary Optic Neuropathy (LHON) Subjects.

Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.

Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm.

Leber Hereditary Optic Neuropathy (LHON) is a primary inherited neurodegenerative disorder of the optic nerve. It has been ascribed to variants in the mitochondrial genome, mainly the m.3460G > A, m.11778G > A and m.14484T > C mutations in ND1, ND4 and ND6 respectively. Nonetheless, inconclusive molecular diagnosis is not uncommon. Recently, biallelic mutations in the NDUFS2, DNAJC30, MCAT and NDUFA12 nuclear genes have been identified in unresolved LHON cases, identifying an autosomal recessive LHON (arLHON, OMIM:619382). The clinical presentation of arLHON copies that of typical mtLHON, with an acute phase of sudden and severe vision loss, telangiectatic and tortuous vessels around the optic nerve, and swelling of the retinal nerve fiber layer (RNFL). This is followed by a chronic phase of RNFL loss, but eventually, affected individuals recovered partial or full visual acuity. Idebenone treatment significantly improved vision recovery in DNAJC30-associated patients. As mtLHON, arLHON predominantly affected male as compared to female carriers. The discovery of arLHON cases breaks with the dogma of exclusive maternal inheritance. It defines a new neuro-ophthalmo-genetic paradigm which should be considered in individuals manifesting a LHON phenotype, but inconclusive molecular diagnosis. NDUFS2, DNAJC30, MCAT and NDUFA12 should be investigated in these individuals, knowing that other arLHON genes might exist.

Protection of dystrophic muscle cells using Idebenone correlates with the interplay between calcium, oxidative stress and inflammation.

There is strong cross-talk between abnormal intracellular calcium concentration, high levels of reactive oxygen species (ROS) and an exacerbated inflammatory process in the dystrophic muscles of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). In this study, we investigated effects of Idebenone, a potent anti-oxidant, on oxidative stress markers, the anti-oxidant defence system, intracellular calcium concentrations and the inflammatory process in primary dystrophic muscle cells from mdx mice. Dystrophic muscle cells were treated with Idebenone (0.05 μM) for 24 h. The untreated mdx muscle cells were used as controls. The MTT assay showed that Idebenone did not have a cytotoxic effect on the dystrophic muscle cells. The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H2 O2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells. These outcomes supported the use of Idebenone as a protective agent against oxidative stress and related signalling mechanisms involved in dystrophinopathies, such as DMD.