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.
OBJECTIVE: 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 Aβ1-42 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.
CONCLUSIONS: 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.
OBJECTIVE: 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 Aβ1-42 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.
CONCLUSIONS: 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.
摘要：
背景：G蛋白偶联受体40（GPR40）是阿尔茨海默病（AD）的潜在药物靶标，其激动剂GW9508通过静脉给药改善认知障碍。
目的：本研究旨在研究GW9508对链脲佐菌素（STZ）诱导的AD小鼠认知功能障碍的影响。
方法：将70只雄性ICR小鼠随机分为7组：载体假手术组，模型，多奈哌齐,GW9508-L,GW9508-M,GW9508-H,和GW1100+GW9508-H组，并分别在第1天和第3天通过侧脑室内注射每天一次(上午9:00)给予载体(人工脑脊液[aCSF])或STZ(在载体中3mg/kg)。经过两周的恢复，所有小鼠均给予药物治疗。行为实验用于测试小鼠的识别和空间记忆，而蛋白质印迹等分子生物学实验，ELISA,和Nissl染色检测信号通路的相应变化。
结果：腹膜内施用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上调肠脑肽如PYY的表达，CCK,IGF-1和GLP-1均在血液循环和脑中通过激活Akt/mTOR信号通路下调自噬相关蛋白的表达水平。同时,GPR40拮抗剂GW1100明显逆转GW9508的治疗效果。
结论：GW9508的外周给药具有神经保护作用，它可能是一种有希望的AD治疗方法。GW9508的神经保护机制是基于促进肠脑肽分泌，激活Akt/mTOR信号通路，调节神经元自噬。
目的：本研究旨在研究GW9508对链脲佐菌素（STZ）诱导的AD小鼠认知功能障碍的影响。
方法：将70只雄性ICR小鼠随机分为7组：载体假手术组，模型，多奈哌齐,GW9508-L,GW9508-M,GW9508-H,和GW1100+GW9508-H组，并分别在第1天和第3天通过侧脑室内注射每天一次(上午9:00)给予载体(人工脑脊液[aCSF])或STZ(在载体中3mg/kg)。经过两周的恢复，所有小鼠均给予药物治疗。行为实验用于测试小鼠的识别和空间记忆，而蛋白质印迹等分子生物学实验，ELISA,和Nissl染色检测信号通路的相应变化。
结果：腹膜内施用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上调肠脑肽如PYY的表达，CCK,IGF-1和GLP-1均在血液循环和脑中通过激活Akt/mTOR信号通路下调自噬相关蛋白的表达水平。同时,GPR40拮抗剂GW1100明显逆转GW9508的治疗效果。
结论：GW9508的外周给药具有神经保护作用，它可能是一种有希望的AD治疗方法。GW9508的神经保护机制是基于促进肠脑肽分泌，激活Akt/mTOR信号通路，调节神经元自噬。
