基于p38丝裂原活化蛋白激酶通路的胰高血糖素样肽-1对大鼠脑缺血再灌注损伤的影响及机制

目的基于p38丝裂原活化蛋白激酶(p38MAPK)通路探讨胰高血糖素样肽-1(GLP-1)对大鼠脑缺血再灌注(I/R)损伤的影响及机制。方法将雄性SD大鼠分为假手术组、模型组、GLP-1组和p38MAPK抑制剂组,每组12只。模型组、GLP-1组和p38MAPK抑制剂组通过大脑中动脉栓塞及再灌注建立脑I/R损伤模型,GLP-1组给予利拉鲁肽(70μg/kg)、p38MAPK抑制剂组给予p38MAPK抑制剂SB202190(10μmol/L、5μl)干预。比较四组大鼠的脑梗死体积、水迷宫行为参数及梗死脑组织细胞凋亡率、氧化应激指标、炎症细胞因子、p38MAPK通路分子的差异。结果与模型组比较,GLP-1组和p38MAPK抑制剂组大鼠的脑梗死体积明显降低,逃避潜伏期明显缩短、穿越平台次数明显增多,梗死脑组织中的细胞凋亡率及丙二醛(MDA)、超氧化物歧化酶(SOD)、TNF-α、IL-1β、IL-6、p-p38水平显著减少,SOD、谷胱甘肽过氧化物酶(GPx)水平明显增加(均P<0.05),p-ERK1/2、p-JNK的表达水平无明显变化。与假手术组比较,模型组大鼠的逃避潜伏期明显延长、穿越平台次数明显减少,梗死脑组织的细胞凋亡率及MDA、ROS、TNF-α、IL-1β、IL-6、p-p38水平明显增高,SOD、GPx水平明显减少(均P<0.05),p-ERK1/2、p-JNK的表达水平无明显变化。结论GLP-1能够通过抑制p38介导的氧化应激及炎症反应减轻大鼠脑I/R损伤。

Effect and mechanism of glucagon-like peptide-1 on cerebral ischemia-reperfusion injury of rats based on p38 mitogen-activated protein kinase pathway

Objective To investigate the effects and mechanism of glucagon-like peptide-1(GLP-1)on cerebral ischemia-reperfusion(I/R)injury in rats based on p38 mitogen-activated protein kinase(p38 MAPK)pathway.Methods Male SD rats were divided into sham group,model group,GLP-1 group and p38 MAPK inhibitor group,12 rats in each group.Brain I/R injury model was established by middle cerebral artery embolization and reperfusion in the latter three groups.Liraglutide(70μg/kg)was given in GLP-1 group,and p38 MAPK inhibitor SB202190(10μmol/L,5μl)was given in p38 MAPK inhibitor group.The differences of cerebral infarction volume,water maze behavior parameter,apoptotic rate,oxidative stress index,inflammatory cytokines and p38 MAPK pathway molecule in infarcted brain tissue were compared among the four groups.Results Compared with those in model group,the cerebral infarction volume of rats in GLP-1 group and p38 MAPK inhibitor group were significantly smaller,escape latency were significantly shorter,the number of times of crossing the platform were significantly increased,the apoptotic rate,contents of malondialdehyde(MDA),superoxide dismutase(SOD),TNF-α,IL-1β,IL-6 and the expression level of p-p38 in infarcted brain tissue were significantly lower,the contents of SOD and glutathione peroxidase(GPx)were significantly higher(all P<0.05).There was no significant difference in the expression levels of p-JNK,p-ERK1/2 between the three groups.Compared with those in sham group,the escape latency in model group were significantly longer,the number of times of crossing the platform were significantly decreased,the apoptotic rate,contents of MDA,ROS,TNF-α,IL-1β,IL-6 and the expression level of p-p38 in infarcted brain tissue were significantly higher,the contents of SOD and GPx were significantly lower(all P<0.05).There was no significant difference in the expression levels of p-JNK,p-ERK1/2 between the two groups.Conclusion GLP-1 can alleviate brain I/R injury by inhibiting p38-mediated oxidative stress and inflammation.