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西格列汀通过糖原合酶激酶-3β通路调控阿尔茨海默病OACSTPCD

Sitagliptin Regulates Alzheimer's Disease through the Glycogen Synthase Kinase-3β Pathway

中文摘要英文摘要

目的:探索西格列汀通过糖原合酶激酶-3β(GSK-3β)通路调控阿尔茨海默病(AD)的机制.方法:72只大鼠随机分为9组第Ⅰ组(对照组):口服饮用水8周;第Ⅱ组(假手术):第1天,大鼠双侧脑室内各输注4 μL人工脑脊液;第Ⅲ组(Aβ1-42):第1天大鼠大脑双侧脑室内各输注4μgAβ1-42;第Ⅳ、Ⅴ、Ⅵ组(Aβ1-42+西格列汀):第1天,大鼠双侧海马输注4 μg Aβ1-42,然后口服不同剂量的西格列汀8周(第Ⅳ、Ⅴ、Ⅵ组西格列汀的剂量分别为1 mg/kg、2 mg/kg、3 mg/kg);第Ⅶ组(西格列汀):口服西格列汀(1 mg/kg)8周;第Ⅷ组(Aβ1-42+多奈哌齐):第1天,大鼠双侧脑室内输注4 μg Aβ 1-42,然后口服多奈哌齐(1 mg/kg)8周;第Ⅸ组(多奈哌齐):口服多奈哌齐(1 mg/kg)8周.造模完成后,采用Morris水迷宫测试各种大鼠记忆功能.再处死大鼠,分别测定各组大鼠海马中的胰高血糖素样肽-1(GLP-1)、可溶性Aβ1-42、胰岛素受体底物-1(IRS-1)(s307)、GSK-3β、乙酰胆碱酯酶(AChE)、过氧化氢酶(CAT)、促炎细胞因子白细胞介素-6(IL-6)、IL-1β和肿瘤坏死因子-α(TNF-α)的水平;行海马HE和刚果红染色,进行病理分析.结果:水迷宫测试结果显示,AD模型组(Ⅲ组)大鼠的找台时间和游泳距离均高于假手术组(Ⅱ组)(均P<0.001);海马GLP-1水平、CAT水平低于假手术组(Ⅱ组)(P<0.01),可溶性Aβ1-42、GSK-3β、IL-6、IL-1β、TNF-α水平均高于假手术组(Ⅱ组)(均P<0.01);HE和刚果红染色结果显示AD模型组(Ⅲ组)细胞浸润性斑块物质较多,有典型的淀粉样蛋白沉积.高剂量(3 mg/kg)西格列汀AD模型组(Ⅵ组)和多奈哌齐AD模型组(Ⅷ组)大鼠的找台时间和游泳距离均低于其他模型组(均P<0.001);大鼠海马GLP-1水平、CAT水平高于其他模型组(均P<0.05),可溶性Aβ1-42、GSK-3β、IL-6、IL-1β、TNF-α水平,IRS-1和IRS-1(s307)表达水平,AChE水平均低于其他模型组(均P<0.05);高剂量西格列汀AD模型组(Ⅵ组)大鼠海马的GLP-1水平高于多奈哌齐AD模型组(Ⅷ组)、TNF-α水平低于多奈哌齐AD模型组(Ⅷ组);HE和刚果红染色结果显示高剂量西格列汀AD模型组(Ⅵ组)和多奈哌齐AD模型组(Ⅷ组)浸润性物质较AD模型组(Ⅲ组)减少,细胞偏向正常,细胞质嗜酸性染色较少,淀粉样蛋白沉积减少.结论:口服8周西格列汀(3 mg/kg)可改善AD大鼠记忆功能,减轻大脑胰岛素抵抗、减轻炎症反应、减少海马神经元的AD样改变,其机制可能与调控GSK-3β信号通路有关.

Objective:To explore the mechanism by which sitagliptin regulates Alzheimer's disease(AD)through the glycogen synthase kinase-3 β(GSK-3 β)pathway.Methods:72 rats were randomly divided into 9 groups.Group Ⅰ(control):oral drinking water for 8 weeks;Group Ⅱ(sham operation):on day 1,each lateral ven-tricle of the rat was infused with 4 μL artificial cerebrospinal fluid;Group Ⅲ(Aβ1-42):on day 1,each lateral ven-tricle of the rat brain was infused with 4 μg Aβ1-42;Groups Ⅳ,Ⅴ,Ⅵ(Aβ1-42+sitagliptin):on day 1,each hippo-campus of the rat was infused with 4 μg Aβ 1-42,then orally administered different doses of sitagliptin for 8 weeks(the doses of sitagliptin for Groups Ⅳ,Ⅴ,and Ⅵ were 1 mg/kg,2 mg/kg,and 3 mg/kg respectively);GroupⅦ(sitagliptin):orally administered sitagliptin(1 mg/kg)for 8 weeks;Group Ⅷ(Aβ1-42+donepezil):on day 1,each lateral ventricle of the rat was infused with 4 μg Aβ 1-42,then orally administered donepezil(1 mg/kg)for 8 weeks;Group Ⅸ(donepezil):orally administered donepezil(1 mg/kg)for 8 weeks.After modeling was complet-ed,the memory function of various rats was tested using the Morris water maze.The rats were then sacrificed,and the levels of glucagon-like peptide-1(GLP-1),soluble Aβ1-42,insulin receptor substrate-1(IRS-1)(s307),GSK-3 β,acetylcholinesterase(AChE),catalase(CAT),proinflammatory cytokines interleukin-6(IL-6),IL-1 β,and tumor necrosis factor-α(TNF-α)in the hippocampus of each group were determined;hippocampal HE and Congo red staining were performed for pathological analysis.Results:Water maze test results showed that the platform finding time and swimming distance of rats in the AD model group(Group Ⅲ)were higher than those in the sham operation group(Group Ⅱ)(both P<0.001);the levels of hippocampal GLP-1 and CAT were lower than those in the sham operation group(Group Ⅱ)(P<0.01),and the levels of soluble Aβ1-42,GSK-3β,IL-6,IL-1 β,TNF-α were all higher than those in the sham operation group(Group Ⅱ)(all P<0.01);HE and Congo red staining results showed that the AD model group(Group Ⅲ)had more cellular infiltration plaque material and typical amyloid protein deposition.The platform finding time and swimming distance of rats in the high-dose(3 mg/kg)sitagliptin AD model group(Group Ⅵ)and donepezil AD model group(Group Ⅷ)were lower than those in other model groups(both P<0.001);the levels of rat hippocampal GLP-1 and CAT were higher than those in other model groups(both P<0.05),and the levels of soluble Aβ1-42,GSK-3β,IL-6,IL-1β,TNF-α,IRS-1,and IRS-l(s307)expres-sion,and AChE were all lower than those in other model groups(all P<0.05);the level of GLP-1 in the hippocampus of rats in the high-dose sitagliptin AD model group(Group Ⅵ)was higher than that in the donepezil AD model group(Group Ⅷ),and the level of TNF-α was lower than that in the donepezil AD model group(Group Ⅷ);HE and Congo red staining results showed that the infiltration material in the hippocampus of rats in the high-dose sitagliptin AD model group(Group Ⅵ)and donepezil AD model group(Group Ⅷ)was reduced compared to the AD model group(Group Ⅲ),cells were more normal,cytoplasmic acidophilic staining was less,and amy-loid protein deposition was reduced.Conclusion:Oral administration of sitagliptin(3 mg/kg)for 8 weeks can improve the memory func-tion of AD rats,reduce brain insulin resistance,alleviate inflammatory response,and reduce AD-like changes in hippocampal neurons,which may be related to the regulation of the GSK-3β signaling pathway.

刘潺潺;李婷;王钟情;张立波;吴本清;朱勇;张丽华;王清勇

深圳市光明区人民医院神经内科,广东 深圳 518106深圳市光明区人民医院急诊科,广东 深圳 518106深圳市光明区人民医院新生儿科 广东 深圳 518106

临床医学

阿尔茨海默病;西格列汀;多奈哌齐;细胞因子

Alzheimer's disease;sitagliptin;donepezil;cytokines

《神经损伤与功能重建》 2024 (004)

187-191,226 / 6

广东省医学科学技术研究基金项目(基于GSK-3β信号通路探索西格列汀调控阿尔茨海默病机制,No.A2022550)

10.16780/j.cnki.sjssgncj.20230548

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