过氧化物酶体增殖物激活受体γ在保护大鼠脑缺血中的作用

摘要

目的：探讨过氧化物酶体增殖物激活受体γ（ peroXisome proliferator-activated receptor gamma，PPARγ）对大鼠脑缺血的保护作用及其机制。方法线栓法建立大鼠右侧大脑中动脉闭塞（ middle cerebral artery occlusion， MCAO）模型。实验分为假手术组、溶剂对照组、替米沙坦组、替米沙坦+GW9662组。采用Western Blot和RT-PCR观察大鼠脑缺血后24h时PPARγ、色素上皮源性生长因子（ pigment epithelium-derived factor，PEDF）、基质金属蛋白酶9（matriX metalloproteinase-9，MMP-9）的基因和蛋白表达变化，采用干湿法测定各组脑组织含水量，采用TTG染色法测定患侧脑梗死体积，采用改良Longna分级法评价神经功能。结果 MCAO后24h，溶剂对照组PPARγ、PEDF表达明显减少，而MMP-9显著增加；替米沙坦组替米沙坦激活PPARγ能够上调PEDF、下调MMP-9，并明显改善神经功能缺失，减轻脑水肿，减小梗死体积，保护缺血脑组织；替米沙坦+GW9662组合并应用PPARγ特异性阻断剂GW9662显著逆转上述保护作用。结论 PPARγ是调控脑缺血后炎症反应的关键性因子，激活PPARγ途径可能成为治疗脑缺血的新靶点。%OcjectiVe This study is to eXplore peroXisome proliferator-activated receptor gamma ( PPARγ)protecting rat brain against focal cerebral ischemic stroke and its mechanism. Methods Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion( MCAO ). Sprague-Dawley rats were randomly divided into four groups:sham-operated group,vehicle group,telmisartan group,and telmisartan+GW9662 group. At 24h after focal cerebral ischemia,the eXpression of PPARγ, pigment epithelium-derived factor(PEDF),matriX metalloproteinase-9(MMP-9)were eXplored by western blot and RT-PCR. The water content of brain tissue was measured by dry-wet weight method,the infarct volume was detected by TTC stain,and the nerve functions were evaluated with the improved Longva method. Results At 24h after MCAO PPARγ and PEDF eXpression significantly decreased,while MMP-9 increased in vehicle group. Telmisartan activating PPARγ dramatically up-regulated PEDF and down-regulated MMP-9,alleviated the neurological deficits,brain water content and infarct volume in telmisartan+GW9662 group,which were all abolished by GW9662 blocking PPARγas shown in telmisartan+GW9662 group. Conclusion PPARγ is the key factor in modulating the inflammatory reactions secondary to focal cerebral ischemia. PPARγ might be the potential therapeutic target for focal cerebral ischemia.