RESUMEN
Leber hereditary optic neuropathy (LHON) is caused by mitochondrial DNA mutations and is the most common inherited mitochondrial disease. It is responsible for central vision loss in young adulthood. However, the precise mechanisms of onset are unknown. This study aimed to elucidate the mechanisms underlying LHON pathology and to discover new therapeutic agents. First, we assessed whether rotenone, a mitochondrial complex â inhibitor, induced retinal degeneration such as that in LHON in a mouse model. Rotenone decreased the thickness of the inner retina and increased the expression levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and immunoglobulin heavy-chain binding protein (BiP). Second, we assessed whether rotenone reproduces LHON pathologies on RGC-5, a neural progenitor cell derived from the retina. Rotenone increased the cell death rate, ROS production and the expression levels of ER stress markers. During chemical compounds screening, we used anti-oxidative compounds, ER stress inhibitors and anti-inflammatory compounds in a rotenone-induced in vitro model. We found that SUN N8075, an ER stress inhibitor, reduced mitochondrial ROS production and improved the mitochondrial membrane potential. Consequently, the ER stress response is strongly related to the pathologies of LHON, and ER stress inhibitors may have a protective effect against LHON.
Asunto(s)
Compuestos de Anilina/farmacología , Descubrimiento de Drogas , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/fisiología , Atrofia Óptica Hereditaria de Leber/tratamiento farmacológico , Atrofia Óptica Hereditaria de Leber/genética , Piperazinas/farmacología , Rotenona/efectos adversos , Animales , Células Cultivadas , ADN Mitocondrial/genética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Estrés del Retículo Endoplásmico/genética , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Mutación , Atrofia Óptica Hereditaria de Leber/inducido químicamente , Atrofia Óptica Hereditaria de Leber/patología , Especies Reactivas de Oxígeno/metabolismo , Retina/efectos de los fármacos , Retina/metabolismo , Retina/patología , Degeneración Retiniana/inducido químicamente , Degeneración Retiniana/genética , Degeneración Retiniana/patologíaRESUMEN
PURPOSE: We report a case of Leber hereditary optic neuropathy in a patient who was using ephedra alkaloids at the time of onset of his optic neuropathy. DESIGN: Observational case report. METHODS: Bilateral, painless, progressive loss of vision developed in a 30-year-old man. He reported a one pack-per day, 10-year history of tobacco use and drinking 18 to 24 cans of beer per day as well as the use of a dietary supplement containing ephedra and caffeine before the onset of vision loss. RESULTS: We report the bilateral, progressive, painless loss of vision in a patient with bilateral cecocentral scotomas and optic nerve pallor. Mitochondrial DNA testing confirmed a Leber hereditary optic neuropathy mutation site at loci 11778. CONCLUSIONS: We propose that our patient's use of a dietary supplement containing ephedra alkaloids played an additive role to his tobacco and alcohol use in causing stress to the already abnormal mitochondrial function, and thereby contributed to the onset of his optic neuropathy. We recommend that patients and families with known Leber hereditary optic neuropathy should be asked about the use of over-the-counter drugs or supplements, and it may be prudent to advise patients against using such dietary supplements.