罗格列酮对2型糖尿病大鼠局灶性脑缺血损伤的保护作用及其机制

Protective effect of rosiglitazone on focal cerebral ischemia injury in type 2 diabetic rats and its mechanism

目的:从内质网应激(ERS)的角度探讨过氧化物酶体增殖物激活受体γ(PPAR-γ)配体罗格列酮(RSG)对2型糖尿病(T2DM)大鼠局灶性脑缺血损伤的作用,并阐明其机制。方法:72只雄性SD大鼠通过高脂高糖饮食4周、尾静脉注射小剂量链脲佐菌素(STZ)25.0mg.kg-1制备T2DM大鼠模型,将制模成功的糖尿病大鼠随机分为假手术组、对照组、RSG组、RSG+GW9662组,每组18只。各组经给药预处理后,均通过线栓法制作大鼠大脑中动脉阻塞(MCAO)模型。假手术组手术步骤同上,但不插入线栓。大鼠于脑缺血后24h处死,对各组大鼠进行神经行为学评分,采用HE染色观察脑组织的病理形态,免疫组织化学法和Western blotting法测定葡萄糖调节蛋白78(GRP78)和C/EBP环磷酸腺苷反应元件结合转录因子同源蛋白(CHOP)的表达,RT-PCR法检测GRP78mRNA和CHOP mRNA的表达。结果:与对照组比较,RSG组大鼠脑缺血后的神经功能缺损明显改善,差异有统计学意义(P<0.01);而RSG+GW9662组与对照组比较差异无统计学意义(P>0.05);与对照组比较,RSG组GRP78表达明显增加(P<0.01);CHOP表达降低(P<0.01);RSG+GW9662组GRP78表达无明显降低(P>0.05);CHOP的表达略增高(P>0.05)。结论:PPAR-γ激动剂RSG对T2DM大鼠局灶性脑缺血损伤具有保护作用,其机制可能与上调GRP78的表达和拮抗CHOP的表达有关。

Objective To study the effect of peroxisome proliferators-activated receptor-γ（PPAR-γ） ligands rosiglitazone（RSG） on focal cerebral ischemia injury in type 2 diabetic（T2DM） rats from the endoplasmic reticulum stress（ERS） perspectives and to clarify its mechanism.Methods 72 male SD rats were fed with high amounts of sugars and fats for 4 weeks,then the low-dose STZ（25.0 mg·kg-1） was injected into caudal vein to make T2DM rat models,the model rats were divided into four groups randomly：sham operation group（n=18）,control group（n=18）,RSG group（n=18） and RSG＋GW9662 group（n=18）.The MCAO models were made after the rats in each group were pretreated by drugs.The surgical procedure in sham operation group was the same as the above,but no thread inserted.The rats were executed 24 h after cerebral ischemia,the neuroethology evaluations for the rats in each group were made,and the pathomorphology of brain tissue in rats was observed by HE staining,the expressions of glucose-regulated protein 78（GRP78） and C/EBP homologous protein（CHOP）were detected by immunohistochemical and Western blotting,and the expressions of GRP78 mRNA and CHOP mRNA were detected by RT-PCR.Results The nerve function defect after cerebral ischemia improved obviously in RSG group compared with control group（P〈0.01）;there were no statistically significant differences between RSG＋GW9662 group and control group（P〉0.05）.The GRP78 expression in RSG group was higher than that in control group（P〈0.05）,however,the CHOP expression in RSG group was lower than that in control group（P〈0.05）;RSG＋GW9662 group showed opposite trend compared with RSG group.Conclusion PPAR-γ agonist RSG has the protective effect on focal cerebral ischemia injury of T2DM rats and the mechanism may be related with up-regulating the GRP78 expression and decreasing the CHOP expression.