Neuroprotection effect of Y-27632 against H2O2- induced cell apoptosis of primary cultured cortical neurons
Neuroprotection effect of Y-27632 against H2O2- induced cell apoptosis of primary cultured cortical neurons
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Y-27632对H2O2诱导的原代培养皮层神经元细胞凋亡的神经保护作用
DOI：
10.1039/c6ra03284b
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Guodong Gao
中科院分区：
文献类型：
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作者：
Xingqin Wang;Bao Wang;Zhenzhen Li;Gang Zhu;Lijun Heng;Xianke Zhu;Qian Yang;Jie Ma;Guodong Gao
氧化应激介导的神经元损伤被认为在缺血的发病机制和结果中起重要作用。Y-27632是一种Rho相关激酶（ROCK）抑制剂，据报道可保护多种细胞免受氧化损伤。然而，Rho激酶抑制剂是否可以直接保护神经元免受氧化损伤及其分子机制知之甚少。本研究探讨了Y-27632对H_2O_2诱导的培养大鼠皮层神经元凋亡的保护作用及其机制，细胞活力试验和细胞凋亡实验均表明Y-27632对H_2O_2诱导的培养大鼠皮层神经元损伤具有保护作用。此外，接下来确定了保护作用的机制。我们的研究结果表明，Y-27632预处理通过抑制H2 O2诱导的抗凋亡蛋白Bcl-2的减少和促凋亡蛋白Bax水平的增加来调节凋亡相关蛋白。同时，Y-27632还显著降低H2 O2诱导的氧化应激以及JNK 1/2/3和p38 MAPK的活化，而不影响ERK 1/2的磷酸化。此外，通过SP 600125和SB 203580分别抑制JNK和p38通路，可减轻H2 O2诱导的细胞活力丧失，并显著质疑Y-27632对H2 O2诱导的细胞凋亡的神经保护作用。综上所述，这些结果表明，Y-27632可以直接保护培养的皮质神经元H2 O2诱导的细胞凋亡，抑制氧化应激和激活JNK和p38 MAPK途径。我们的研究为Y-27632的治疗机制提供了有用的见解，并进一步支持ROCK是神经系统疾病的一个有前途的药物靶点。
Oxidative stress-mediated neuron damage is believed to contribute greatly to the pathogenesis and outcome of ischemia. Y-27632, a Rho-associated kinase (ROCK) inhibitor, has been reported to protect various cells from oxidative injury. However, whether a Rho-kinase inhibitor can directly protect neurons against oxidative damage and the molecular mechanisms underlying it is poorly understood. In the present study, we investigated the potential protective effect of Y-27632 against H2O2-induced apoptosis in cultured rat cortical neurons and potential mechanisms underlying it. Both the cell viability tests and cell apoptosis assays showed that Y-27632 effectively protected the cultured rat cortical neurons from H2O2-induced injury. Furthermore, the mechanisms underlying the protective effect were determined next. Our results revealed that Y-27632 pretreatment regulated the apoptosis-related proteins by inhibiting the H2O2-induced decrease in anti-apoptotic protein Bcl-2 and an increase in the level of pro-apoptotic protein Bax. Meanwhile, Y-27632 also significantly reduced oxidative stress and the activation of JNK1/2/3 and p38 MAPKs induced by H2O2, without affecting the phosphorylation of ERK1/2. Moreover, inhibiting the JNK and p38 pathways by SP600125 and SB203580 respectively alleviated the cell viability loss induced by H2O2 and markedly disputed the neuroprotective effect of Y-27632 against H2O2-induced apoptosis. Taken together, these results demonstrate that Y-27632 can directly protect cultured cortical neurons from H2O2-induced apoptosis by inhibiting oxidative stress and the activation of JNK and p38 MAPKs pathways. Our study provides useful insights into the therapeutic mechanisms of Y-27632 and further supports that ROCK is a promising drug target for neurological diseases.