氯沙坦对脑缺血-再灌流损伤保护作用的实验研究

Protective effect of AT_1 receptor antagonist on focal cerebral ischemia-reperfusion in rats

目的 研究氯沙坦对脑缺血再灌流大鼠神经功能的影响。方法 32只Wistar大鼠被随机分为氯沙坦用药组、缺血再灌流组、假手术组和正常对照组 ,每组各 8只。用药组给予氯沙坦 (10mg·kg-1·d-1)灌胃 ,其余 3组给予生理盐水灌胃。 2周后制作大鼠大脑中动脉栓塞模型 ,缺血 4h再灌流 2h后断头处死 ,处死前进行神经功能评分 ,用TUNEL法检测神经细胞凋亡 ,免疫组织化学法检测神经细胞c fos、c jun蛋白的表达。结果 氯沙坦用药组神经功能评分、细胞凋亡率及c fos和c jun阳性细胞率均明显低于未用药缺血再灌流组 (P <0 0 5 )。结论 氯沙坦可抑制脑缺血再灌流诱导的c fos、c jun蛋白表达和细胞凋亡并降低神经功能评分 ,对脑缺血再灌流损伤有一定保护作用。

Objective To test the effect of the selective AT 1 receptor antagonist on the recovery from focal cerebral ischemia reperfusion,apoptosis and expression of c fos and c jun.Methods Thirty two 8 week old male Wistar rats were divided into four groups.The selective AT 1 receptor antagonist-Losartan(10mg·kg -1 ·d -1 )was given as a pretreatment for 2 weeks in experiment group( n =8) and equal 0 9% saline solution in vehicle group( n =8).Focal cerebral ischemia was induced by middle cerebral artery occlusion lasting for 4 hours and followed by reperfusion for 2 hours.Sham operated rats ( n =8)and normal rats not subjected to any surgical procedure served as controls ( n =8).Neurological outcome was evaluated and coronal brain sections were examined by hematoxylin and eosin.Apoptosis was analyzed by TdT mediated dUTP biotin nick end labeling and image analysis system.Expression of c fos and c jun were measured by immuno histochemical methods and image analysis system.Results Focal brain ischemia resulted in a strong induction of apoptosis,c fos and c jun protein in the cortex(all P <0 05),which positively correlated with the degree of neurological deficits(all P <0 05).Apoptosis were located primary in the frontal parietal cortex and striatum.pretreat with Losartan significantly improved neurological outcome of focal cerebral ischemia compared with vehicle group and markedly reduced the expression of apoptosis,c fos and c jun protein in the ischemia side of the brain( P <0 05,respectively).Conclusion Pretreatment with an AT 1 receptor antagonist has beneficaial effects on brain.Blockage of AT 1 receptor improves the recovery from focal cerebral ischemia reperfusion and reduces apoptosis and expression of c fos and c jun,which have been implicated in the regulation of apoptosis.