Abstract: Objective　To investigate the effects of etomidate on cognitive function and oxidative stress in Alzheimer's disease mice by regulating mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) signaling pathway. Methods　The study was conduct from May 2020 to September 2021.In this study, fifty APP/PS1 transgenic mice were divided into a model group, low, medium, and high dose of etomidate groups, and a positive control group, ten SPF grade C57BL/6 mice were used as control. Among them, the low, medium, and high dose of etomidate groups were given gavage with 1.0, 2.5, and 5.0 mg/kg of etomidate, the positive control group was given gavage with 10 mg/kg of donepezil hydrochloride, and the model group and control group were given gavage with an equal volume of normal saline, 1 time/d, for 30 d. The Morris water maze test was used to observe the learning and memory abilities of the mice, and the nerve injury score and brain tissue water content of the mice were measured; Western blot was used to detect the expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-10, IL-1β, and MAPK/ERK signaling pathway-related proteins in mouse brain tissue; enzyme-linked immunosorbent assay (ELISA) was used to detect the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA) in mouse brain tissue. One-way analysis of variance was used to compare the measurement data among multiple groups, and LSD-t test was used for further pairwise comparison. Results　Compared with those of the control group, the escape latency of the model group was significantly prolonged, the number of cross-platforms, the platform area stay distance, and the activities of SOD, CAT, and GSH-Px were decreased, the nerve injury score, brain tissue water content, and MDA content were increased, the protein expressions of TNF-α, IL-10, and IL-1β were up-regulated, and the protein expressions of phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2 and p-p38 were down-regulated (all P<0.05). Compared with those of the model group, the escape latency of the low, medium, and high dose of etomidate groups were significantly shortened, the numbers of cross-platform, platform area stay distances, and activities of SOD, CAT, and GSH-Px were increased, the nerve injury scores, brain tissue water contents, and MDA contents were decreased, the protein expressions of TNF-α, IL-10, and IL-1β were down-regulated, and the protein expressions of p-ERK1/2 and p-p38 were up-regulated (all P<0.05). Conclusion　Etomidate may improve the cognitive function in Alzheimer's disease mice by increasing MAPK/ERK signaling pathway, and reduce the oxidative stress and inflammatory response in mouse brain tissue.

Key words: Etomidate, MAPK/ERK signaling pathway, Alzheimer's disease, Cognitive function, Oxidative stress

摘要： 目的　探究依托咪酯通过调控丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）信号通路对阿尔茨海默病小鼠认知功能和氧化应激的影响。方法　本研究院于2020年5月至2021年9月进行。将50只APP/PS1转基因小鼠分为模型组，依托咪酯低、中、高剂量组，阳性对照组，10只SPF级C57BL/6小鼠作为对照组，其中依托咪酯低、中、高剂量组分别给予1.0、2.5、5.0 mg/kg依托咪酯灌胃，阳性对照组给予10 mg/kg盐酸多奈哌齐灌胃，模型组、对照组给予等体积生理盐水灌胃，1次/ d，灌胃30 d。采用Morris水迷宫实验观察小鼠学习、记忆能力，并测定小鼠神经损伤评分、脑组织含水量；蛋白免疫印迹法（Western blot）检测小鼠脑组织肿瘤坏死因子（TNF）-α、白细胞介素（IL）-10、IL-1β、MAPK/ERK信号通路相关蛋白表达；酶联免疫吸附法（ELISA）检测小鼠脑组织超氧化物歧化酶（SOD）活性、过氧化氢酶（CAT）活性、谷胱甘肽过氧化物酶（GSH-Px）活性、丙二醛（MDA）含量。计量资料多组间比较采用单因素方差分析，进一步组内间比较用LSD-t检验。结果　与对照组相比，模型组的逃避潜伏期均明显延长，跨平台次数、平台区停留距离、SOD活性、CAT活性、GSH-Px活性均降低，神经损伤评分、脑组织含水量、MDA含量均增加，上调TNF-α、IL-10、IL-1β蛋白表达，下调磷酸化细胞外信号调节激酶（p-ERK）1/2、p-p38蛋白表达（均P<0.05）；与模型组比较，依托咪酯低、中、高剂量组的逃避潜伏期均明显缩短，跨平台次数、平台区停留距离、SOD活性、CAT活性、GSH-Px活性均升高，神经损伤评分、脑组织含水量、MDA含量均降低，并下调TNF-α、IL-10、IL-1β蛋白表达，上调p-ERK1/2、p-p38蛋白表达（均P<0.05）。结论　依托咪酯可能通过增加MAPK/ERK信号通路改善阿尔茨海默病小鼠认知功能，并减轻小鼠脑组织氧化应激和炎性反应。

关键词: 依托咪酯, MAPK/ERK信号通路, 阿尔茨海默病, 认知功能, 氧化应激