Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy

Klopstock, Thomas; Metz, Günther; Yu‐Wai‐Man, Patrick; Büchner, Boriana; Gallenmüller, Constanze; Bailie, Maura; Nwali, Nwanyieze; Griffiths, PG; von, Livonius; Reznicek, Lukas; Rouleau, Jacinthe; Coppard, N; Meier, Thomas; Chinnery, Patrick F.

doi:10.1093/brain/aws279

Cited by 166 publications

(99 citation statements)

References 11 publications

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“…However, many in vivo studies showed much potential of idebenone against oxidative stress in the eye [12,52,53] and other organs [13,21,54]. Antioxidants already are a major pillar of AMD therapy, but they are still not fully satisfactory.…”

Section: Discussionmentioning

confidence: 99%

Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio

et al. 2015

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Purpose: Age-related macular degeneration (AMD) is one of the leading causes of blindness. Degeneration of the retinal pigment epithelium (RPE) is pathognomonic for the disease, and oxidative stress plays an important role in the pathogenesis of this disease. This study investigates potential antiapoptotic and cytoprotective effects of idebenone on cultured RPE cells (ARPE-19) under conditions of oxidative stress. Methods: ARPE-19 cells were treated with 1-100 µM idebenone. Cell viability (MTT assay), induction of intracellular reactive oxygen species (ROS) and histone-associated DNA fragments in mono- and oligonucleosomes, expression of proapoptotic BAX and antiapoptotic Bcl-2 as well as senescence-associated β-galactosidase (SA-β-Gal) activity were investigated under exposure to hydrogen peroxide (H₂O₂). Results: Idebenone concentrations from 1 to 20 µM showed no toxic effects on ARPE-19 cells. When cells were treated with H₂O₂, pretreatment with 5, 7.5, 10, and 20 µM idebenone led to a significant increase in the viability of ARPE-19 cells. In addition, idebenone pretreatment significantly attenuated the induction of SA-β-Gal and intracellular ROS as well as the amount of histone-associated DNA fragments after treatment with H₂O₂. The reduction of proapoptotic BAX and the elevation of antiapoptotic Bcl-2 under idebenone show that this process is rather mediated by inhibiting H₂O₂-induced apoptosis, not necrosis. Conclusion: In this study, idebenone increased survival of ARPE-19 cells and reduced cell death, senescence, and oxidative stress by stabilizing the BAX/Bcl-2 ratio.

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Section: Discussionmentioning

confidence: 99%

Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio

et al. 2015

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“…More hydrosoluble molecules than ubiquinone have been developed and tested in different diseases; for example, the short-chain quinone idebenone, a synthetic derivative of CoQ10, has been shown to prevent cardiac hypertrophy in Friedreich's ataxia (119) and to improve measures of cognitive scores in patients with AD (351). Recently, idebenone has been awarded a temporary authorization and awaits marketing authorization for the treatment of Leber's Hereditary Optic Neuropathy, an inherited mitochondrial disease (Raxone Ò ; Santhera Pharmaceuticals) (150). Another strategy to preserve redox balance and an adequate mitochondrial function is the induction of endogenous antioxidants, and the Nrf-2 antioxidant signaling pathway is among the most eligible ones for this purpose.…”

Section: Non-targeted Antioxidant Treatmentsmentioning

confidence: 99%

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

Apostolova

Víctor

2015

Antioxidants & Redox Signaling

235

147

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Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid-and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686-729.

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“…Idebenone at a dose of 900 mg/day was used for 24 weeks in a multicenter clinical trial of 85 patients and included individuals with up to a 5-year history of the disease (ClinicalTrials.gov identifier: NCT00747487) (Klopstock et al 2011). The primary end point of visual acuity was not achieved in this study; however, there was a trend of visual improvement in the treated group, and if there were discordant visual acuities in the two eyes at the disease onset, then there may have been a beneficial effect in the less affected eye (Klopstock et al 2013). EPI-743 showed a benefit in a small trial of five patients .…”

Section: Leber Hereditary Optic Neuropathy (Lhon)mentioning

confidence: 59%

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Narayanan

Kuppermann

2016

Handbook of Experimental Pharmacology

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Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy

Cited by 166 publications

References 11 publications

Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio

Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

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