Lei Dawei, Shao Zhengbo, Zhou Xinrong, Yuan Huiping
Department of Ophthalmology, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
Oncotarget. 2018 Jan 30;9(15):12137-12153. doi: 10.18632/oncotarget.24343. eCollection 2018 Feb 23.
Retinal ischemia-reperfusion (RIR) injury causes neuronal degeneration and initiates various optic nerve diseases. This study aimed to investigate the synergistic neuroprotective effect of rasagiline and idebenone against RIR injury. A combination of rasagiline and idebenone was administered intraperitoneally immediately after establishment of the RIR model. Treatment with the combination of the two drugs resulted in a significant restoration of retinal thickness and retinal ganglion cells. Apoptosis of cells in ganglion cell layers was also ameliorated, suggesting that the effect of the two drugs was synergistic and the expression of brain-derived neurotrophic factor increased. Furthermore, idebenone and rasagiline induced the expression of Lin28A and Lin28B, respectively, which resulted in a reduced expression of microRNAs in the let-7 family and an increased protein output of Dicer. The data obtained from gene overexpression and knockdown experiments indicated that let-7 and Dicer were necessary for the synergistic neuroprotective effect of the two drugs. Our findings suggested that combination therapy with rasagiline and idebenone produced a synergistic effect that ameliorated RIR injury and restored visual function. In addition, the combined treatment provided neuroprotection via enhancement of the selective regulation of let-7 by Lin28A/B. These findings implied that a treatment with the combination of rasagiline and idebenone is a feasible treatment option for optic nerve diseases.
视网膜缺血再灌注（RIR）损伤会导致神经元变性，并引发各种视神经疾病。本研究旨在探讨雷沙吉兰和艾地苯醌对RIR损伤的协同神经保护作用。在建立RIR模型后立即腹腔注射雷沙吉兰和艾地苯醌的组合。两种药物联合治疗导致视网膜厚度和视网膜神经节细胞显著恢复。神经节细胞层细胞的凋亡也得到改善，表明两种药物的作用具有协同性，且脑源性神经营养因子的表达增加。此外，艾地苯醌和雷沙吉兰分别诱导Lin28A和Lin28B的表达，这导致let-7家族微小RNA的表达减少以及Dicer的蛋白质产量增加。基因过表达和敲低实验获得的数据表明，let-7和Dicer是两种药物协同神经保护作用所必需的。我们的研究结果表明，雷沙吉兰和艾地苯醌联合治疗产生了协同效应，改善了RIR损伤并恢复了视觉功能。此外，联合治疗通过增强Lin28A/B对let-7的选择性调控提供神经保护。这些发现意味着雷沙吉兰和艾地苯醌联合治疗是视神经疾病的一种可行治疗选择。
