利拉鲁肽通过激活过氧化物酶体增殖物激活受体改善合并糖尿病的局灶性脑缺血损伤  

Liraglutide protects against focal cerebral ischemic injury with diabetes mellitus by activating peroxisome proliferator-activated receptors

作　　者：何婧[1] 韩江全[1] 施宁华[1] 刘婷 郭琪琪 He Jing;Han Jiangquan;Shi Ninghua;Liu Ting;Guo Qiqi(Department of Neurology,The Fifth Affiliated Hospital of Zunyi Medical College)

机构地区：[1]遵义医学院第五附属(珠海)医院神经内科,珠海519100

出　　处：《重庆医科大学学报》2020年第3期350-355,共6页Journal of Chongqing Medical University

基　　金：珠海市重点学科资助项目(编号:珠卫20088013);遵义市科技计划资助项目(编号:遵市科合社字〔2018〕20号)。

摘　　要：目的:通过观察利拉鲁肽对糖尿病大鼠脑缺血损伤后脑组织中过氧化物酶体增殖物激活受体表达的影响,进一步探讨利拉鲁肽如何影响合并糖尿病的脑缺血损伤及可能机制。方法:48只成年雄性Sprague-Dawley大鼠随机分为假手术组(Sham组)、糖尿病脑缺血组(DCI组)、利拉鲁肽组(Lir组)、胰岛素组(Ins组),每组12只。应用链脲佐菌素腹腔注射诱发糖尿病,继而制作永久性大脑中动脉闭塞模型。Lir组、Ins组于缺血前7 d分别腹腔注射利拉鲁肽(100μg/kg,q12h)、胰岛素(2 U/kg,q12h),其他各组于同一时间段腹腔注射等量生理盐水。脑缺血24 h后作神经功能评分,断头取脑行2,3,5-氯化三苯四氮唑(2,3,5-triphenyl tetrazolium chloride,TTC)染色测脑梗死面积,蛋白印迹法检测缺血区PPARα(peroxisome proliferator-activated receptorα)、PPARβ、PPARγ、NF-κB、p65、TNF-α的表达情况。结果:各组药物干预前后血糖同组比较:Lir组、Ins组注射利拉鲁肽、胰岛素后血糖水平明显下降,注射前后均有统计学差异(P=0.000;P=0.008)。神经功能缺损评分:Sham组无神经功能缺损,与DCI相比,Ins组神经功能评分无明显改变;而Lir组明显降低(P=0.000)。TTC染色:Sham组未见梗死灶,与DCI组相比,Ins组梗死灶无明显变化,而Lir组梗死体积明显缩小(P=0.033)。蛋白质印迹显示:PPARα、PPARβ、PPARγ、NF-κBp65、TNF-α表达水平在Sham组、DCI组、Ins组和Lir组各组间存在统计学差异(F=15.826,P=0.000;F=21.988,P=0.000;F=21.132,P=0.000;F=21.023,P=0.000;F=63.607,P=0.000)。与DCI组相比,Ins组各组蛋白表达无统计学差异。而Lir组PPARα、PPARβ、PPARγ表达明显增高(P=0.000;P=0.000;P=0.000),NF-κBp65、TNF-α表达明显降低(P=0.000;P=0.000)。结论:利拉鲁肽对糖尿病大鼠局灶性脑缺血损伤具有一定的保护作用,其可能机制与上调PPARα、PPARβ、PPARγ表达,下调NF-κBp65、TNF-α表达有关。Objective:To observe the effect of liraglutide on the expression of peroxisome proliferator-activated receptors(PPARs)in the brain tissue of diabetic rats after cerebral ischemic injury,and to further investigate the effect of liraglutide on cerebral ischemic injury with diabetes mellitus and the possible mechanism.Methods:Forty-eight adult male Sprague-Dawley rats were randomly divided into four groups:sham-operated group(Sham group),diabetes cerebral ischemia group(DCI group),liraglutide-pretreatment DCI group(Lir group),and insulin-pretreatment DCI group(Ins group),with 12 rats in each group.Diabetes was induced by intraperitoneal injection of streptozotocin,and a model of permanent middle cerebral artery occlusion(MCAO)was established in the diabetic rats.The rats in the Lir group and Ins group were intraperitoneally injected with liraglutide(100μg/kg,q12h)and insulin(2 U/kg,q12h),respectively,7 days before MCAO,while the other two groups were injected with an equal volume of normal saline during the same period of time.Neurological deficit scores were determined at 24 hours after MCAO.Then the rats were decapitated,and their brain tissues were taken out to measure the infarct area by TTC staining.Western blotting was used to measure the expression of PPARα,PPARβ,PPARγ,nuclear factor-kappa Bp65(NF-κB p65),and tumor necrosis factor-α(TNF-α)in the ischemic area.Results:The Lir group and Ins group showed significant reductions in blood glucose after injection of liraglutide or insulin(P=0.000,P=0.000).The Sham group showed no neurological deficit;compared with the DCI group,the Ins group had no significant change in neurological deficit score,but the Lir group showed a significant reduction in neurological deficit score(P=0.008).TTC staining showed that no infract was observed in the Sham group;compared with the DCI group,the Ins group had no significant change in infarct volume,but the Lir group showed a significant reduction in infarct volume(P=0.033).Western blot showed significant differences in the e

关 键 词：利拉鲁肽 糖尿病 脑缺血 胰岛素 过氧化物酶体增殖物激活受体 炎症反应 

分 类 号：R743.3[医药卫生—神经病学与精神病学]