Simvastatin Protects Photoreceptors from all-trans-retinal Induced Oxidative Stress with Up-regulation of Interphotoreceptor Retinoid Binding Protein

摘要： Background and Purpose Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with multiple targets and effects. It protects neurons in the brain but its protective effects on photoreceptors are unclear. In this study, we evaluated the neuroprotective effect of simvastatin on photoreceptors exposed to stress induced by all-trans-retinal (atRAL). Experimental approach AlamarBlue and lactate dehydrogenase assays were used to evaluate the viability and metabolic activity of Y79 cells (a retinoblastoma cell line) exposed to atRAL-induced stress with or without simvastatin pre-treatment. Changes in cellular reactive oxygen species were evaluated using flow cytometry and mitochondrial stress markers JC-1 and HSP60. Changes in levels of the photoreceptor-specific markers cone-rod homeobox protein (CRX) and Interphotoreceptor Retinoid Binding Protein (IRBP) were evaluated with Western blotting. The results were validated in ex vivo human retinal explants and a mouse model of photoreceptor degeneration. Key results Simvastatin improved mitochondrial function, alleviated oxidative stress and upregulated the photoreceptor specific markers IRBP and its upstream regulator CRX in Y79 cells and ex vivo human retinal explants under atRAL-induced stress. Simvastatin attenuated photoreceptor degeneration in association with upregulation of IRBP and CRX expression after knockdown of IRBP in a murine model. Conclusion and implications Our findings suggest that simvastatin has a novel role in protecting photoreceptors from atRAL-induced stress. Simvastatin treatment resulted in upregulation of IRBP and its upstream transcription factor CRX in Y79 cells, ex vivo human retinal explants and murine retinas in vivo. Further studies of simvastatin to treat photoreceptor degeneration are warranted.