Idebenone Protects against Retinal Damage and Loss of Vision in a Mouse Model of Leber’s Hereditary Optic Neuropathy

Abstract

Leber’s hereditary optic neuropathy (LHON) is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC) dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON. It was therefore of interest to study suitable LHON models in vitro and in vivo to identify anatomical correlates for this protective activity. At nanomolar concentrations, idebenone protected the rodent RGC cell line RGC-5 against complex I dysfunction in vitro. Consistent with the reported dosing and observed effects in LHON patients, we describe that in mice, idebenone penetrated into the eye at concentrations equivalent to those which protected RGC-5 cells from complex I dysfunction in vitro. Consequently, we next investigated the protective effect of idebenone in a mouse model of LHON, whereby mitochondrial complex I dysfunction was caused by exposure to rotenone. In this model, idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, idebenone restored the functional loss of vision in this disease model. These results support the pharmacological activity of idebenone and indicate that idebenone holds potential as an effective treatment for vision loss in LHON patients.

Leber’s hereditary optic neuropathy - Case report

“…In this model, idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, idebenone restored the functional loss of vision in this disease model [16]. After a 3 months treatment, we observed a slightly increase of VA and an improvement in contrast sensitivity in our patients.…”

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

“…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.…”

Idebenone treatment in Leber's hereditary optic neuropathy: rationale and efficacy

“…Due to its balanced lipophilicity (log D = 3.9) [44], idebenone can repeatedly cross membranes, such as the mitochondrial membranes, and can be re-activated by cytoplasmic NQO1, which allows idebenone to re-establish ATP levels in cells with impaired complex I function. The observation that idebenone protects the retinal ganglion cell line RGC5 against mitochondrial complex I inhibition supports this model [46]. This mechanism of action also explains why idebenone cannot be substituted by other antioxidants or by CoQ 10 , which is exclusively located within membranes.…”

“…Importantly, the authors also demonstrated that orally administered idebenone penetrated rapidly into the eye fluids within minutes and most importantly also protected against loss of vision in this animal model [46].…”