Neuroprotective effect of WIN 55,212-2 pretreatment against focal cerebral ischemia through activation of extracellular signal-regulated kinases in rats.
Neuroprotective effect of WIN 55,212-2 pretreatment against focal cerebral ischemia through activation of extracellular signal-regulated kinases in rats.
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DOI：
10.1016/j.ejphar.2010.07.024
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发表时间：
2010-10
影响因子：
5
通讯作者：
Bo Hu;Qiang Wang;Ye Chen;Juan Du;Xiao-ling Zhu;Yan Lu;L. Xiong;Shao-yang Chen
中科院分区：
文献类型：
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作者：
Bo Hu;Qiang Wang;Ye Chen;Juan Du;Xiao-ling Zhu;Yan Lu;L. Xiong;Shao-yang Chen
大麻素受体激动剂WIN 55,212-2对脑缺血损伤具有保护作用。我们之前的研究表明，WIN 55,212-2预处理以剂量依赖的方式诱导局灶性脑缺血的缺血耐受。本研究的目的是研究WIN 55,212-2预处理的时间效应关系，并探讨磷酸化的细胞外信号调节激酶1/2的作用。用1mg/kg WIN 55,212-2预处理大鼠，每天1次，连续1、3、5天。预处理结束24小时后，阻断大脑中动脉致局灶性脑缺血。以神经功能评分和脑梗死体积评价脑缺血损伤。研究了有丝分裂原活化蛋白激酶激酶的有效特异性抑制剂U0126对WIN 55,212-2预处理的影响。免疫组化和Western blotting检测缺血侧半暗区再灌注4h后磷酸化的细胞外信号调节激酶1/2的表达。结果表明，WIN 55,212-2预处理对大鼠脑短暂性局灶性缺血损伤具有保护作用，且随着预处理次数的增加，其保护作用逐渐增强，U0126可部分逆转。我们进一步发现，WIN 55,212-2预处理上调了磷酸化的细胞外信号调节激酶1/2的水平。这些结果提示，WIN 55,212-2预处理对大鼠局灶性脑缺血的神经保护作用是通过激活细胞外信号调节激酶实现的。
It is well documented that cannabinoid receptor agonist WIN 55,212-2 had protective effect against cerebral ischemic injury. Our previous study indicated that WIN 55,212-2 pretreatment induced ischemic tolerance to focal cerebral ischemia in a dose-dependent manner. The aim of the present study was to investigate the time–effect relationship of the WIN 55,212-2 pretreatment and explore the role of phosphorylated extracellular signal-regulated kinase 1/2. Rats were pretreated with 1mg/kg WIN 55,212-2 once a day for 1, 3 and 5days. Twenty four hours after the end of pretreatment, focal cerebral ischemia was induced by the middle cerebral artery occlusion. Brain ischemic injury was evaluated by neurological function scores and infarction volumes. The effect of U0126, a potent and specific inhibitor of mitogen-activated protein kinase kinase, on WIN 55,212-2 pretreatment was also studied. Moreover, the expression of phosphorylated extracellular signal-regulated kinase 1/2 in the penumbra of ischemic side 4h after reperfusion was investigated by immunohistochemistry and Western blotting. The results showed that WIN 55,212-2 pretreatment can protect the rat brain against transient focal cerebral ischemia injury, and its protective effect was enhanced gradually with increasing numbers of pretreatment, and was partially reversed by U0126. We further found that WIN 55,212-2 pretreatment up-regulated the levels of phosphorylated extracellular signal-regulated kinase 1/2. These findings suggest that the neuroprotective effect of WIN 55,212-2 pretreatment against focal cerebral ischemia is through the activation of extracellular signal-regulated kinases in rats.