Liu Sha, Ji Yuke, Li Huan, Ren Ling, Zhu Junya, Yang Tianjing, Li Xiumiao, Yao Jin, Cao Xin, Yan Biao
The Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210093, China.
The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210093, China.
Pharmaceuticals (Basel). 2023 Jul 20;16(7):1033. doi: 10.3390/ph16071033.
Retinal neurodegeneration is a major cause of vision loss. Retinoic acid signaling is critical for the maintenance of retinal function, and its dysfunction can cause retinal neurodegeneration. However, the therapeutic effects of retinoic acid drugs on retinal neurodegeneration remain unclear. In this study, we designed a novel retinoic acid drug called EYE-503 and investigated its therapeutic effects of EYE-503 on retinal neurodegeneration. The optic nerve crush (ONC) model was selected for the retinal neurodegeneration study. H&E staining, TUNEL staining, immunofluorescence staining, and visual electrophysiology assays were performed to determine the role of EYE-503 in retinal neurodegeneration in vivo. The CCK-8 assay, EdU incorporation assay, PI staining, and flow cytometry assays were performed to investigate the effects of EYE-503 administration on retinal neurodegeneration in vitro. The potential mechanism of EYE-503 in retinal neurodegeneration was investigated by network pharmacology and Western blots. The results showed that EYE-503 administration had no detectable cytotoxicity and tissue toxicity. EYE-503 administration alleviated ONC-induced retinal injury and optic nerve injury in vivo. EYE-503 administration attenuated retinal ganglion cell apoptosis, inhibited reactive gliosis, and retarded the progression of retinal neurodegeneration. Mechanistically, EYE-503 regulated retinal neurodegeneration by targeting the JNK/p38 signaling pathway. This study suggests that EYE-503 is a promising therapeutic agent for retinal neurodegenerative diseases.
视网膜神经变性是视力丧失的主要原因。视黄酸信号传导对于维持视网膜功能至关重要，其功能障碍可导致视网膜神经变性。然而，视黄酸药物对视网膜神经变性的治疗效果仍不清楚。在本研究中，我们设计了一种名为EYE-503的新型视黄酸药物，并研究了其对视网膜神经变性的治疗效果。选择视神经挤压（ONC）模型进行视网膜神经变性研究。进行苏木精-伊红（H&E）染色、末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）染色、免疫荧光染色和视觉电生理测定，以确定EYE-503在体内视网膜神经变性中的作用。进行细胞计数试剂盒-8（CCK-8）测定、5-乙炔基-2'-脱氧尿苷（EdU）掺入测定、碘化丙啶（PI）染色和流式细胞术测定，以研究给予EYE-503对体外视网膜神经变性的影响。通过网络药理学和蛋白质免疫印迹法研究EYE-503在视网膜神经变性中的潜在机制。结果表明，给予EYE-503没有可检测到的细胞毒性和组织毒性。给予EYE-503可减轻体内ONC诱导的视网膜损伤和视神经损伤。给予EYE-503可减轻视网膜神经节细胞凋亡，抑制反应性胶质增生，并延缓视网膜神经变性的进展。机制上，EYE-503通过靶向JNK/p38信号通路调节视网膜神经变性。本研究表明，EYE-503是一种有前途的治疗视网膜神经退行性疾病的药物。
