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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.
关键词： photoreceptors,IRBP,CRX,oxidative stress,all-trans-retinal,Simvastatin
更新于2025-11-21 11:08:12
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Effects of Simvastatin on Retinal Structure and Function of a High-Fat Atherogenic Mouse Model of Thickened Bruch's Membrane
摘要： PURPOSE. To determine the effect of a statin (simvastatin) on the ultrastructure and function of the RPE, Bruch’s membrane (BM), and photoreceptor interface in a high-fat atherogenic mouse model of thickened BM. METHODS. Wild-type C57BL/6 mice (6-weeks old) were divided into three study groups according to their diet and treatment given; Group 1, normal chow diet-fed mice; Group 2, high fat diet (HFD) fed mice; and Group 3, HFD-fed mice treated with simvastatin daily for 30 weeks. All mice were followed-up for 30 weeks. The retinal morphology and function was examined in vivo using fundus imaging and electroretinography at 15- and 30-weeks follow-up. At the end of the study, at 36 weeks of age, eye tissues were collected and retinal sections were examined using light microscopy and transmission electron microscopy. RESULTS. Fundus images of the HFD-fed mice showed the presence of discrete, multiple white spots, which was signi?cantly reduced by approximately 73% in the simvastatin-treated animals. In the HFD-fed mice, there was an increase in the empty cytoplasmic vacuoles of the RPE, presence of lipid droplets in the BM, thickening and fragmentation of the elastic lamina of the BM, and a reduction in retinal function; these ultrastructural and functional changes were signi?cantly improved in the simvastatin-treated group. CONCLUSIONS. Chronic administration of simvastatin signi?cantly improves the ultrastructure and function of the RPE, BM, and photoreceptor in a high-fat atherogenic mouse model of thickened BM.
关键词： electroretinography,Bruch’s membrane,simvastatin,high-fat atherogenic mouse model,retina
更新于2025-09-09 09:28:46