Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
Eur J Pharmacol. 2021 Oct 15;909:174362. doi: 10.1016/j.ejphar.2021.174362. Epub 2021 Jul 21.
The functions and mechanisms of GPR40 receptor to ameliorating the Alzheimer's disease (AD) by external treatment of encephalopathy remain unknown. In present study, the typical Aβ induced mice model was applied to explore the functions and mechanisms of GPR40 receptor by external treatment of encephalopathy in AD. GPR40 agonist GW9508 and antagonist GW1100 were given by i.g injection to activate/inhibit the GPR40 receptor respectively in the gut of AD mouse which illustrated the function and mechanism of GPR40 receptor in ameliorating AD symptoms by external treatment of encephalopathy. A series of behavioral experiments were used to investigate the cognitive function and memory ability of mice, while molecular biology experiments such as Western blot, ELISA, flow cytometry were used to detect the corresponding changes of signaling pathways. The results revealed that intragastric administrated GW9508 could significantly ameliorate cognitive deficits of AD mouse, up-regulate the expression levels of gut-brain peptides both in blood circulation and hypothalamus thus up-regulate the expression levels of α-MSH in hypothalamus, while the negative autophagy-related proteins and inflammation-related proteins were down-regulated correspondingly. Meanwhile, GW9508 could also inhibit the pathological process of neuroinflammation in microglia. GW1100 reversed the effects of GW9508 significantly. These results suggested that GPR40 was an underlying therapeutic target for the external treatment of encephalopathy related to AD and GPR40 agonist could be explored as the emerging AD therapeutic drug.
GPR40 受体通过肠外治疗脑病改善阿尔茨海默病（AD）的功能和机制尚不清楚。本研究应用典型的 Aβ 诱导的小鼠模型，探讨了 GPR40 受体通过肠外治疗脑病对 AD 的作用及其机制。通过肠道内给予 GPR40 激动剂 GW9508 和拮抗剂 GW1100 分别激活/抑制 AD 小鼠肠道中的 GPR40 受体，说明了 GPR40 受体在改善 AD 症状的肠外治疗中的作用和机制。通过一系列行为学实验研究了小鼠的认知功能和记忆能力，同时通过 Western blot、ELISA、流式细胞术等分子生物学实验检测了相应的信号通路变化。结果表明，灌胃给予 GW9508 可显著改善 AD 小鼠的认知障碍，上调血循环和下丘脑内的肠-脑肽表达水平，从而上调下丘脑内的α-MSH 表达水平，同时相应地下调自噬相关蛋白和炎症相关蛋白的表达水平。此外，GW9508 还能抑制小胶质细胞神经炎症的病理过程。GW1100 则显著逆转了 GW9508 的作用。这些结果表明，GPR40 是一种潜在的治疗 AD 相关肠外治疗的靶点，GPR40 激动剂可作为新型 AD 治疗药物进行探索。
