PPARδ激动剂GW501516对大鼠脑缺血再灌注损伤的影响  

Effects of PPARδagonist GW501516 on cerebral ischemia-reperfusion injury in rats

作　　者：李咏 刘立[1] LI Yong;LIU Li(Department of Pharmacy,Wuhan NO.4 Hospital,Wuhan 430033,China)

机构地区：[1]武汉市第四医院药学部,武汉430033

出　　处：《山西医科大学学报》2023年第2期208-214,共7页Journal of Shanxi Medical University

基　　金：武汉市卫健委医学科研项目(WX20B05)。

摘　　要：目的探讨过氧化物酶体增殖物激活受体δ(PPARδ)激动剂GW501516对大鼠脑缺血再灌注(I/R)损伤的影响及其调控机制。方法将48只SD大鼠随机分成假手术组(sham)、模型组(model)、PPARδ激动剂GW501516干预组(GW,0.05 mg/kg)、GW501516+AMPK抑制剂Dorsomorphin干预组(GW+Dor,0.05 mg/kg GW501516+0.25 mg/kg Dorsomorphin),每组12只。除sham组外,其余各组均采用双侧颈总动脉夹闭合并低血压法建立大鼠脑I/R模型,并于造模前30 min经侧脑室分别注射相应药物进行干预。I/R 24 h后,采用Zea-Longa评分法评估大鼠神经功能损伤情况;HE染色观察大鼠脑缺血半暗带区病理学变化;TUNEL染色检测大鼠脑缺血半暗带区细胞凋亡情况;免疫荧光观察大鼠脑缺血半暗带区LC3Ⅱ阳性表达情况;Western blot检测大鼠脑缺血半暗带区PPARδ、AMPKα、p-AMPKα(Thr172)、Beclin-1、LC3蛋白表达水平。结果与sham组比较,model组大鼠神经功能及脑缺血半暗带区损伤严重,脑缺血半暗带区中细胞凋亡、LC3Ⅱ阳性细胞数量及Beclin-1蛋白和p-AMPKα/AMPKα、LC3Ⅱ/Ⅰ蛋白比值水平均明显升高(P<0.05),而PPARδ蛋白表达水平明显降低(P<0.05);与model组比较,GW组大鼠神经功能及脑缺血半暗带区损伤均明显缓解,脑缺血半暗带区中LC3Ⅱ阳性细胞数量及PPARδ、Beclin-1蛋白和p-AMPKα/AMPKα、LC3Ⅱ/Ⅰ蛋白比值水平均明显升高(P<0.05),而细胞凋亡明显降低(P<0.05);与GW组比较,GW+Dor组大鼠神经功能及脑缺血半暗带区损伤加重,脑缺血半暗带区中细胞凋亡明显升高(P<0.05),LC3Ⅱ阳性细胞数量及Beclin-1蛋白和p-AMPKα/AMPKα、LC3Ⅱ/Ⅰ蛋白比值水平均明显降低(P<0.05),而PPARδ蛋白表达水平无明显变化(P>0.05)。结论早期给予PPARδ激动剂GW501516干预可通过激活AMPK信号通路介导的细胞自噬改善大鼠脑I/R损伤。Objective To explore the effects of peroxisome proliferators-activated receptorδ(PPARδ)agonist GW501516 on cerebral ischemia-reperfusion(I/R)injury in rats and its regulatory mechanism.Methods A total of 48 SD rats were randomly divided into sham operation group,model group,PPARδagonist GW501516 intervention group(GW group,0.05 mg/kg),and GW501516+AMPK inhibitor Dorsomorphin intervention group(GW+Dor group,0.05 mg/kg GW501516+0.25 mg/kg Dorsomorphin),with 12 rats in each group.Brain I/R model in the other groups was established by closing bilateral common carotid artery and hypotensive method,and the corresponding drugs were injected through the lateral ventricle 30 min before modeling.Zea-Longa scoring method was used to evaluate the neurological impairment of rats 24 h after I/R;HE staining was used to observe the pathological changes in cerebral ischemic penumbra of rats;TUNEL staining was used to detect the apoptosis of cells in cerebral ischemic penumbra of rats;immunofluorescence was used to observe the positive expression of LC3Ⅱin cerebral ischemic penumbra of rats;Western blot was used to detect the protein expression levels of PPARδ,AMPKα,p-AMPKα(Thr172),Beclin-1 and LC3 in cerebral ischemic penumbra of rats.Results Compared with sham group,the neurological function and the cerebral ischemic penumbra of rats were severely damaged in model group,and the cell apoptosis,the number of LC3Ⅱpositive cells,the protein expression level of Beclin-1 and the protein ratios of p-AMPKα/AMPKαand LC3Ⅱ/Ⅰin cerebral ischemic penumbra of rats were significantly increased in model group(P<0.05),while the protein expression level of PPARδin cerebral ischemic penumbra of rats was significantly decreased(P<0.05).Compared with model group,the damage of neurological function and cerebral ischemic penumbra of rats were significantly alleviated in GW group,and the number of LC3Ⅱpositive cells,the protein expression level of PPARδand Beclin-1 and the protein ratios of p-AMPKα/AMPKαand LC3Ⅱ/Ⅰin cerebral i

关 键 词：脑缺血再灌注损伤 过氧化物酶体增殖物激活受体Δ AMPK信号通路 自噬 

分 类 号：R743[医药卫生—神经病学与精神病学]