利拉鲁肽影响海马组织核因子E2相关因子2/谷胱甘肽过氧化物酶4信号通路和铁死亡活性改善阿尔茨海默病大鼠认知障碍的机制研究

To study the mechanism of liraglutide improving cognitive impairment in alzheimer’s disease rats by affecting nuclear factor erythroid 2⁃related factor 2/glutathione peroxidase 4 signaling pathway and ferroptosis activity in hippocampus

目的探讨利拉鲁肽影响海马组织核因子E2相关因子2(Nrf2)/谷胱甘肽过氧化物酶4(GPX4)信号通路和铁死亡活性改善阿尔茨海默病(AD)大鼠认知障碍的机制。方法将40只SD大鼠随机分为对照组、模型组、利拉鲁肽组和利拉鲁肽+erastin组,每组各10只。侧脑室注射脲链佐菌素(STZ)构建AD模型;利拉鲁肽组在AD造模同时每日腹腔注射利拉鲁肽(200μg/kg)连续28 d;利拉鲁肽+erastin组在AD造模同时侧脑室注射erastin(2.5 nmol/g),然后腹腔注射利拉鲁肽(200μg/kg)连续28 d。采用Morris水迷宫检测大鼠认知功能,采用ELISA法检测大鼠海马组织Aβ42和谷胱甘肽(GSH)水平,采用Western blot检测磷酸化Tau蛋白、Nrf2、GPX4蛋白表达水平。结果对照组、利拉鲁肽组、利拉鲁肽+erastin组及模型组大鼠第3 d、4 d和5 d逃逸潜伏期时间均依次延长,穿越平台次数依次减少(P<0.05)。对照组、利拉鲁肽组、利拉鲁肽+erastin组及模型组大鼠海马组织Aβ42水平和Nrf2、GPX4、磷酸化Tau蛋白表达水平均依次升高;对照组、利拉鲁肽+erastin组、利拉鲁肽组及模型组大鼠海马组织GSH水平依次降低(P<0.05)。结论利拉鲁肽可能通过影响海马组织Nrf2/GPX4信号通路和铁死亡活性,参与AD大鼠认知障碍的改善。

Objective To investigate the mechanism of liraglutide improving cognitive impairment in Alzheimer’s disease(AD)rats by affecting nuclear factor erythroid 2⁃related factor 2(Nrf2)/glutathione peroxidase 4(GPX4)signaling pathway and ferroptosis activity in hippocampus.Methods Forty SD rats were randomly divided into control group,model group,liraglutide group and liraglutide+ferroptosis inducer erastin group,with 10 rats in each group.The AD model was established by intracerebroventricular injection of streptozotocin(STZ).The liraglutide group was intraperitoneally injected with liraglutide(200μg/kg)daily for 28 consecutive days.In the liraglutide+erastin group,intracerebroventricular injection of erastin(2.5 nmol/g)was performed simultaneously,followed by intraperitoneal injection of liraglutide(200μg/kg)for 28 consecutive days.Morris water maze was used to detect cognitive function,ELISA was used to detect the levels of Aβ42 and glutathione(GSH)in the hippocampus,and Western blot was used to detect the expression levels of phosphorylated Tau protein,Nrf2 and GPX4 protein.Results The escape latency time of rats in control group,liraglutide group,liraglutide+erastin group and model group was successively prolonged on the 3rd,4th and 5th day,and the frequency of crossing the platform was successively reduced(P<0.05).The level of Aβ42 and the expression levels of Nrf2,GPX4 and phosphorylated Tau protein in the hippocampus of control group,liraglutide group,liraglutide+erastin group and model group were increased in turn,the GSH level in hippocampus of control group,liraglutide+erastin group,liraglutide group and model group was decreased sequentially(P<0.05).Conclusion Liraglutide may be involved in the improvement of cognitive impairment in AD rats by affecting Nrf2/GPX4 signaling pathway and ferroptosis activity in hippocampus.