二甲双胍对阿尔茨海默病大鼠的疗效及机制研究

Efficacy and mechanism of metformin in a rat model of AD

目的观察二甲双胍对阿尔茨海默病(Alzheimer’s disease,AD)大鼠学习记忆能力的影响,并进一步探讨其可能机制。方法将50只雄性SD大鼠随机分为正常组、假手术组、模型组和治疗组。模型组和治疗组大鼠双侧海马各注射5μl Aβ25-35(2 g/L)建立AD模型,假手术组注射等量生理盐水。次日,对治疗组大鼠予以二甲双胍灌胃治疗,100 mg/(kg·d),连续给药2 w。干预结束后,检测各组大鼠学习记忆能力、海马区细胞基本情况及PI3K、AKT、P-AKT、GSK3β、P-GSK3β、tau[pS202]、tau5的相对表达量。结果二甲双胍能显著改善AD模型大鼠的认知能力(P<0.05);各组大鼠海马区细胞基本形态结构无明显差异;与正常组相比,假手术组上述蛋白相对表达量无明显改变,但模型组大鼠海马组织中PI3K、P-AKT/AKT、P-GSK3β/GSK3β的表达情况明显下调(P<0.05),干预后有所改善(P<0.05);模型组中tau[pS202]/tau5明显高于正常组和假手术组,干预后tau蛋白磷酸化程度降低(P<0.05)。结论二甲双胍能够有效改善AD模型大鼠学习记忆能力,其机制可能与“PI3K-AKT-GSK3β-tau磷酸化”信号通路密切相关。

Objective To observe the effects of metformin on learning and memory ability in Alzheimer’s disease(AD)rats,and to further explore the potential mechanism.Methods Fifty male SD rats were randomly divided into normal group,sham group,model group and treatment group.AD model was established by injecting 5μl Aβ25-35(2 g/L)into the hippocampus,and the same amount of normal saline was injected into the sham group rats.The rats in the treatment group were given 100 mg/(kg·d)metformin by gavage for 2 weeks.The next day,the learning and memory ability of rats,the basic conditions of hippocampal cells,and the relative expression levels of PI3K,AKT,P-AKT,GSK3β,P-GSK3β,tau[PS202]and tau5 in hippocampal tissues of rats in each group were detected.Results Metformin significantly improved the cognitive ability of AD model rats(P<0.05).No significant difference in the basic morphological structure of hippocampal cells among all groups was observed.Compared with the normal and sham group,the expression levels of PI3K,P-AKT/AKT,P-GSK3β/GSK3βin the hippocampus of the model rats were significantly down-regulated(P<0.05),which were improved after metformin intervention(P<0.05).The expression of tau[pS202]/tau5 in the model group was significantly higher than that in the normal group and the sham group,and the phosphorylation of tau protein decreased after treatment(P<0.05).Conclusion Metformin can effectively improve the learning and memory ability of AD model rats.Interestingly,the mechanism may be closely related to the“PI3K-AKT-GSK3β-tau phosphorylation”signaling pathway.