利拉鲁肽对致痫小鼠海马神经细胞凋亡的影响

Effects of Liraglutide on Hippocampal Neuronal Apoptosis in Epileptic Mice

目的探讨利拉鲁肽在癫痫发病中的神经保护作用及其机制。方法SPF级雄性C57BL/6小鼠,氯化锂-匹罗卡品致痫成功后,每天给予利拉鲁肽150μg·kg-1腹腔注射,连续2周。实时监测癫痫发作情况,旷场实验、IntelliCage行为学监测系统观察小鼠行为学变化,Western blot检测利拉鲁肽对小鼠海马神经细胞哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、p-mTOR、BCL-2和Cleaved caspase-3蛋白表达的影响。结果与对照组相比,利拉鲁肽降低了匹罗卡品诱导的癫痫小鼠的癫痫发作等级(P<0.01),延长了发作潜伏期(P<0.01),增加了癫痫小鼠旷场实验移动距离(P<0.01),减少了中央区停留时间(P<0.01),并增加IntelliCage行为学监测系统4个阶段访问次数(P<0.05)及鼻触次数(P<0.01);利拉鲁肽降低了p-mTOR/mTOR(P<0.01)及Cleaved caspase-3蛋白的表达(P<0.05),升高了BCL-2蛋白的表达(P<0.01)。结论利拉鲁肽可改善致痫小鼠的焦虑状况和认知能力,并通过mTOR信号通路抑制致痫小鼠海马神经元凋亡来发挥神经保护作用。

Objective To explore the neuroprotective effect and mechanism of liraglutide in epileptic mice.Methods Totally 40 C57BL/6 male mice of SPF grade were used.A lithium chloride-pilocarpine epilepsy model was established,which was divided into normal saline group,normal liraglutide group,experimental group,pilocarpine model group and liraglutide treatment group.150μg·kg-1 of liraglutide was intraperitoneally administered daily for 2 weeks.Seizures were dynamically monitored.The behavioral changes of mice were observed by the open field experiment and IntelliCage experiment.Western blot was used to detect the expression of p-mTOR,mTOR,BCL-2 and Cleaved caspase-3 in each group.Results Compared with the control group,liraglutide reduced the seizure grade of pilocarpine-induced epileptic mice(P<0.01),prolonged the seizure latency(P<0.01),increased the moving distance(P<0.01)and the central zone residence time(P<0.01)in the open field experiment.The number of visits(P<0.05)and nosepoke(P<0.01)in IntelliCage four-stage experiment were significantly increased.At the same time,liraglutide significantly decreased the expression of p-mTOR/mTOR rate(P<0.01)and Cleaved caspase-3(P<0.05),but increased the expression of BCL-2(P<0.01).Conclusion Liraglutide can extenuate the anxiety and improve the cognitive ability by reducing neuronal apoptosis via inhibiting mTOR signaling pathway in epileptic mice.