Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan.
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
FASEB J. 2022 Sep;36(9):e22497. doi: 10.1096/fj.202200455RRR.
Retinal ischemia-reperfusion (I/R) injury is a common cause of visual impairment. To date, no effective treatment is available for retinal I/R injury. In addition, the precise pathological mechanisms still need to be established. Recently, pemafibrate, a peroxisome proliferator-activated receptor α (PPARα) modulator, was shown to be a promising drug for retinal ischemia. However, the role of pemafibrate in preventing retinal I/R injury has not been documented. Here, we investigated how retinal degeneration occurs in a mouse model of retinal I/R injury by elevation of intraocular pressure and examined whether pemafibrate could be beneficial against retinal degeneration. Adult mice were orally administered pemafibrate (0.5 mg/kg/day) for 4 days, followed by retinal I/R injury. The mice were continuously administered pemafibrate once every day until the end of the experiments. Retinal functional changes were measured using electroretinography. Retina, liver, and serum samples were used for western blotting, quantitative PCR, immunohistochemistry, or enzyme linked immunosorbent assay. Retinal degeneration induced by retinal inflammation was prevented by pemafibrate administration. Pemafibrate administration increased the hepatic PPARα target gene expression and serum levels of fibroblast growth factor 21, a neuroprotective molecule in the eye. The expression of hypoxia-response and pro-and anti-apoptotic/inflammatory genes increased in the retina following retinal I/R injury; however, these changes were modulated by pemafibrate administration. In conclusion, pemafibrate is a promising preventive drug for ischemic retinopathies.
视网膜缺血再灌注 (I/R) 损伤是视力损害的常见原因。迄今为止，尚无有效的治疗方法可用于治疗视网膜 I/R 损伤。此外，还需要确定确切的病理机制。最近，过氧化物酶体增殖物激活受体 α (PPARα) 调节剂 pemafibrate 被证明是治疗视网膜缺血的一种有前途的药物。然而，pemafibrate 预防视网膜 I/R 损伤的作用尚未有文献记载。在这里，我们通过升高眼内压研究了视网膜 I/R 损伤小鼠模型中视网膜变性的发生情况，并探讨了 pemafibrate 是否对视网膜变性有益。成年小鼠连续 4 天每天口服 pemafibrate（0.5mg/kg/天），然后进行视网膜 I/R 损伤。每天继续给予 pemafibrate 一次，直到实验结束。使用视网膜电图测量视网膜功能变化。使用 Western blot、定量 PCR、免疫组织化学或酶联免疫吸附试验检测视网膜、肝脏和血清样本。pemafibrate 的给药可预防视网膜炎症引起的视网膜变性。pemafibrate 的给药增加了肝脏中 PPARα 靶基因的表达和血清中神经营养因子成纤维细胞生长因子 21 的水平。视网膜 I/R 损伤后，视网膜中缺氧反应以及促凋亡/促炎和抗凋亡/抗炎基因的表达增加；然而，这些变化可通过 pemafibrate 的给药进行调节。总之，pemafibrate 是一种有前途的缺血性视网膜病变预防药物。
