Synergistic neuroprotective effect of rasagiline and idebenone against retinal ischemia-reperfusion injury via the Lin28-let-7-Dicer pathway.
Synergistic neuroprotective effect of rasagiline and idebenone against retinal ischemia-reperfusion injury via the Lin28-let-7-Dicer pathway.
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雷沙吉兰和艾地苯醌通过 Lin28-let-7-Dicer 途径对视网膜缺血再灌注损伤具有协同神经保护作用。
DOI：
10.18632/oncotarget.24343
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发表时间：
2018-02-23
期刊：
影响因子：
--
通讯作者：
Yuan H
中科院分区：
文献类型：
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作者：
Lei D;Shao Z;Zhou X;Yuan H
视网膜缺血-再灌注（RIR）损伤引起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模型后立即腹膜内施用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的显著恢复。神经节细胞层的细胞凋亡也得到改善，表明两种药物的作用是协同的，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Lin 28 A和Lin 28 B的表达，这导致let-7家族中microRNA的表达减少和Dicer蛋白质输出增加。基因过表达和敲低实验结果表明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，恢复了视功能。此外，联合治疗通过增强Lin 28 A/B对let-7的选择性调节提供神经保护。这些发现表明，雷沙吉兰和艾地苯醌的组合治疗是视神经疾病的可行治疗选择。
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.