Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats

Frontiers in Pharmacology

Pharmacology

Min Wu¹  Chao Liu¹  Jiangyan Zhao¹  Xiaosong Yang¹  Xiufen Liu¹  Zhanhong Ren¹  Min Lei¹  Xiying Guo¹  Qingjie Chen¹  Changhan Ouyang² 

[1] Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China;Pharmacy College, Xianning Medical College, Hubei University of Science and Technology, Xianning, China;

关键词: tirzepatide;    diabetes mellitus;    spatial learning and memory;    Aβ;    synaptic plasticity;    inflammation;    insulin;   

DOI  :  10.3389/fphar.2023.1146960

 received in 2023-01-18, accepted in 2023-08-14,  发布年份 2023

来源: Frontiers

【 摘 要 】

Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes’s impairment of spatial learning memory.Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines.Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide.Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.

【 授权许可】

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Copyright © 2023 Guo, Lei, Zhao, Wu, Ren, Yang, Ouyang, Liu, Liu and Chen.