Delayed treatment with NSC23766 in streptozotocin-induced diabetic rats ameliorates post-ischemic neuronal apoptosis through suppression of mitochondrial p53 translocation
Delayed treatment with NSC23766 in streptozotocin-induced diabetic rats ameliorates post-ischemic neuronal apoptosis through suppression of mitochondrial p53 translocation
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DOI：
10.1016/j.neuropharm.2014.06.008
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发表时间：
2014-10-01
影响因子：
4.7
通讯作者：
Wang, E.
中科院分区：
文献类型：
--
作者：
Liao, Juan;Ye, Zhi;Wang, E.
NSC 23766是Rac 1的特异性抑制剂，最近已被证明可保护脑缺血性损伤，尽管尚未检查NSC 23766在糖尿病模型中的作用。因此，我们研究的目的是研究NSC 23766是否在链脲佐菌素诱导的糖尿病大鼠中提供神经保护，并确定NSC 23766的潜在作用机制。将糖尿病Sprague-Dawley大鼠右侧大脑中动脉闭塞（MCAO）90分钟。从脑缺血后24小时开始，每天两次腹腔内给予NSC 23766（10或30 mg kg（-1））或等渗盐水，连续三天。再灌注后96 h，对脑梗死体积、神经功能缺损评分、神经元凋亡、细胞色素c释放以及ROS生成和线粒体完整性进行评价。此外，p53的线粒体易位和p53上调的细胞凋亡调节因子（p53上调的调节因子A）在脑缺血皮层的线粒体的表达通过蛋白质印迹法测定。NSC 23766不仅能改善糖尿病大鼠脑缺血后神经元凋亡，而且能降低脑缺血诱导的线粒体p53易位和线粒体中p53蛋白A的表达。因此，我们的数据表明，NSC 23766对脑缺血再灌注损伤具有治疗潜力，并且NSC 23766通过抑制链脲佐菌素诱导的糖尿病大鼠中线粒体p53易位而显著改善神经元凋亡。(C)2014爱思唯尔有限公司版权所有。
NSC23766, a specific inhibitor of Rac1, has recently been shown to protect against cerebral ischemic injury, although the effects of NSC23766 in a diabetic model have not been examined. Therefore, the aim of our study was to investigate if NSC23766 provided neuroprotection in streptozotocin-induced diabetic rats and to determine the potential mechanism through which NSC23766 works. Diabetic Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 90 min. NSC23766 (10 or 30 mg kg(-1)) or isotonic saline were administered intraperitoneally twice daily starting 24 h after cerebral ischemia, for three consecutive days. Cerebral infarct volume, neurological deficit scores, neuronal apoptosis, and the release of cytochrome c, as well as the generation of ROS and mitochondrial integrity, were evaluated 96 h after reperfusion. In addition, the mitochondrial translocation of p53 and the expression of p53-upregulated modulator of apoptosis (PUMA) in the mitochondria of the cerebral ischemic cortex were determined by western blotting. NSC23766 not only ameliorated post-ischemic neuronal apoptosis but also decreased cerebral ischemia-induced mitochondrial p53 translocation and the expression of PUMA in mitochondria in diabetic rats. Thus, our data indicate that NSC23766 has therapeutic potential against cerebral ischemic reperfusion injury and that NSC23766 significantly ameliorates neuronal apoptosis by suppressing mitochondrial p53 translocation in streptozotocin-induced diabetic rats. (C) 2014 Elsevier Ltd. All rights reserved.