西格列汀通过糖原合酶激酶-3β通路调控阿尔茨海默病  

Sitagliptin Regulates Alzheimer’s Disease through the Glycogen Synthase Kinase-3βPathway

作　　者：刘潺潺 李婷 王钟情 张立波 吴本清 朱勇 张丽华 王清勇 LIU Chanchan;LI Ting;WANG Zhongqing;ZHANG Libo;WU Benqing;ZHU Yong;ZHANG Lihua;WANG Qingyong(Department of Neurology,Guangdong Shenzhen 518106,China;b.Department of Emergency,Guangdong Shenzhen 518106,China;Department of Neonatology,Guangming District People’s Hospital,Guangdong Shenzhen 518106,China)

机构地区：[1]深圳市光明区人民医院神经内科,广东深圳518106 [2]深圳市光明区人民医院急诊科,广东深圳518106 [3]深圳市光明区人民医院新生儿科,广东深圳518106

出　　处：《神经损伤与功能重建》2024年第4期187-191,226,共6页Neural Injury and Functional Reconstruction

基　　金：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)。

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4μL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4μg Aβ1-42;第IV、V、VI组(Aβ1-42+西格列汀):第1天,大鼠双侧海马输注4μg 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4μg Aβ1-42,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�Objective:To explore the mechanism by which sitagliptin regulates Alzheimer’s disease(AD)through the glycogen synthase kinase-3β(GSK-3β)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 ventricle of the rat was infused with 4μL artificial cerebrospinal fluid;Group III(Aβ1-42):on day 1,each lateral ventricle of the rat brain was infused with 4μg Aβ1-42;Groups IV,V,VI(Aβ1-42+sitagliptin):on day 1,each hippocampus of the rat was infused with 4μg Aβ1-42,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);Group VII(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 4μg Aβ1-42,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 completed,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-3β,acetylcholinesterase(AChE),catalase(CAT),proinflammatory cytokines interleukin-6(IL-6),IL-1β,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-1β,TNF-αwere 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

关 键 词：阿尔茨海默病 西格列汀 多奈哌齐 细胞因子 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学] R742