西格列汀通过糖原合酶激酶-3β通路调控阿尔茨海默病OACSTPCD

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.