GW9508 ameliorates cognitive dysfunction via autophagy pathway in streptozotocin-induced mouse model of Alzheimer's disease

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY Fundamental & Clinical Pharmacology Pub Date : 2024-03-14 DOI:10.1111/fcp.13002

Yanan Wang, Jingjing Chen, Chen Wang, Tong Chen, Ling He

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Abstract

Background

G protein-coupled receptor 40 (GPR40) is a potential drug target for Alzheimer's disease (AD), and its agonist GW9508 ameliorates cognitive impairment by intravenous administration.

Objectives

The present study was conducted to investigate the efficacy of GW9508 administered peripherally on cognitive dysfunction in streptozotocin (STZ)-induced AD mice.

Methods

Seventy male ICR mice were randomly divided into seven groups: vehicle sham group, model, Donepezil, GW9508-L, GW9508-M, GW9508-H, and GW1100 + GW9508-H groups, and administered either vehicle (artificial cerebrospinal fluid [aCSF]) or STZ (3 mg/kg in the vehicle) once a day (9:00 a.m.) by intracerebroventricular injection bilaterally on day 1 and day 3, respectively. After 2 weeks of recovery, all mice were given drug treatment. Behavioral experiments were applied to test the recognition and spatial memory of mice, while molecular biology experiments such as Western blot, ELISA, and Nissl staining were used to detect the corresponding changes of signaling pathways.

Results

Intraperitoneal administration of GW9508 prevented STZ-induced cognitive impairment as well as decreased the level of p-tau and Aβ_1–42 in plasma and brain. GW9508 upregulated the expression of gut-brain peptides like PYY, CCK, IGF-1, and GLP-1 both in blood circulation and brain and downregulated the expression level of autophagy-related proteins through activating Akt/mTOR signaling pathway. Meanwhile, the treatment effect of GW9508 was reversed by GPR40 antagonist GW1100 significantly.

Conclusion

Peripheral administration of GW9508 exhibits neuroprotective effects, and it could be a promising therapy for AD. The neuroprotective mechanism of GW9508 was based on promoting gut-brain peptide secretion, activating Akt/mTOR signal pathway, and regulating neuronal autophagy.

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GW9508通过自噬途径改善链脲佐菌素诱导的阿尔茨海默病小鼠模型的认知功能障碍。

背景：G蛋白偶联受体40（GPR40）是阿尔茨海默病（AD）的潜在药物靶点，其激动剂GW9508通过静脉给药可改善认知障碍：本研究旨在探讨GW9508外周给药对链脲佐菌素（STZ）诱导的AD小鼠认知功能障碍的疗效：将70只雄性ICR小鼠随机分为7组：载体假组、模型组、多奈哌齐组、GW9508-L组、GW9508-M组、GW9508-H组和GW1100 + GW9508-H组，分别于第1天和第3天每天一次（上午9:00）双侧脑室内注射载体（人工脑脊液[aCSF]）或STZ（载体中含3 mg/kg）。恢复 2 周后，对所有小鼠进行药物治疗。行为实验用于检测小鼠的识别和空间记忆能力，分子生物学实验如 Western blot、ELISA 和 Nissl 染色则用于检测信号通路的相应变化：结果：腹腔注射GW9508可预防STZ诱导的认知障碍，并降低血浆和大脑中p-tau和Aβ1-42的水平。GW9508通过激活Akt/mTOR信号通路，上调PYY、CCK、IGF-1和GLP-1等肠脑多肽在血液循环和大脑中的表达，并下调自噬相关蛋白的表达水平。同时，GPR40拮抗剂GW1100能显著逆转GW9508的治疗效果：结论：外周给药 GW9508 具有神经保护作用，有望成为一种治疗 AD 的方法。GW9508的神经保护机制基于促进肠脑多肽分泌、激活Akt/mTOR信号通路和调节神经元自噬。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.