文献类型：期刊文献

中文题名：黑逍遥散调控TMA/FMO3/TMAO代谢通路抑制神经炎症改善APP/PS1小鼠的认知障碍

英文题名：Hei Xiaoyaosan Regulates TMA/FMO3/TMAO Metabolic Pathway to Inhibit Neuroinflammation and Improve Cognitive Impairment in APP/PS1 Mice

作者：杨娇[1];陈怡琴[1];裴文丽[1];韩玉梅[1];王虎平[1,2,3]

第一作者：杨娇

机构：[1]甘肃中医药大学,兰州730000;[2]甘肃省中医方药挖掘与创新转化重点实验室,兰州730000;[3]甘肃省中药新产品创制工程实验室,兰州730000

第一机构：甘肃中医药大学

年份：2025

卷号：31

期号：19

起止页码：171

中文期刊名：中国实验方剂学杂志

外文期刊名：Chinese Journal of Experimental Traditional Medical Formulae

收录：;北大核心:【北大核心2023】；

基金：国家自然科学基金项目(82160862);第五批全国中医临床优秀人才研修项目(国中医药人教函[2022]239号);首批陇原青年英才项目(中共甘肃省委人才工作领导小组[2022]5号)。

语种：中文

中文关键词：阿尔茨海默病;黑逍遥散;三甲胺(TMA)/肝黄素单加氧酶3(FMO3)/氧化三甲胺(TMAO)代谢通路;神经炎症;认知障碍

外文关键词：Alzheimer's disease;Hei Xiaoyaosan;trimethylamine(TMA)/flavin containing monooxygenase 3(FMO3)/trimethylamine N-oxide(TMAO)metabolic pathway;neuroinflammation;cognitive impairment

摘要：目的:该研究探讨黑逍遥散通过调控三甲胺(TMA)/肝黄素单加氧酶3(FMO3)/氧化三甲胺(TMAO)代谢通路对APP/PS1小鼠神经炎症的干预作用。方法:选取4月龄SPF级APP/PS1雄性小鼠60只按随机数字表法分为模型组,双歧杆菌四联活菌片组,盐酸多奈哌齐组及黑逍遥散高、中、低剂量组,连续灌胃90 d;10只同月龄、同系的雄性野生型C57BL/6J小鼠作为空白组。旷场实验检测小鼠的自主活动,Morris水迷宫实验测试小鼠学习记忆能力,尼色染色观察各组小鼠海马神经元的形态,酶联免疫吸附测定法(ELISA)检测小鼠海马组织中白细胞介素(IL)-1β、IL-18和小鼠血清中tau、磷酸化(p)-tau(Thr181)、p-tau(Thr231)、p-tau(Ser262)、p-tau(Ser396)的表达,液相色谱-质谱联用技术(LC-MS)分析检测小鼠血清中TMAO的水平,蛋白免疫印迹法(Western blot)检测小鼠肝脏中FMO3和海马中NOD样受体蛋白3(NLRP3)、凋亡相关斑点样蛋白(ASC)、胱天蛋白酶-1(Caspase-1)蛋白的表达。结果:与空白组比较,模型组小鼠在旷场实验中总路程、进入中央区次数、中央区域活动路程均减少(P<0.01);第3、4天定位航行实验中逃避潜伏期时间延长而穿越平台次数减少(P<0.01);海马神经元细胞结构异常,尼氏体模糊;海马组织中IL-1β、IL-18及血清中tau、p-tau(Thr181)、p-tau(Thr231)、p-tau(Ser262)、p-tau(Ser396)水平及TMAO含量增加(P<0.05,P<0.01);肝脏组织中FMO3蛋白表达上升及海马组织中NLRP3、ASC、Caspase-1蛋白表达上升(P<0.01)。与模型组比较,双歧杆菌四联活菌片组、盐酸多奈哌齐组、黑逍遥散高剂量组小鼠活动的总路程、中央区域活动路程、第3天和第4天的逃避潜伏期降低(P<0.05,P<0.01),进入中央区次数及穿越平台次数均增加(P<0.05,P<0.01);各给药组中海马神经元损伤得到改善、肝脏组织中FMO3蛋白和海马组织中Caspase-1蛋白表达下降及小鼠海马组织中IL-1β、IL-18和小鼠血清中tau、p-tau(Thr181)、p-tau(Thr231)、p-tau(Ser262)、p-tau(Ser396)水平降低(P<0.05,P<0.01);双歧杆菌四联活菌片组、盐酸多奈哌齐组、黑逍遥散中高剂量组小鼠血清中TMAO含量和海马组织中NLRP3和ASC蛋白表达下降(P<0.05,P<0.01)。结论:黑逍遥散可改善APP/PS1小鼠的认知障碍,其作用机制可能与调控TMA/FMO3/TMAO代谢通路以抑制神经炎症有关。
Objective:This study explores the intervention effect of Hei Xiaoyaosan on neuroinflammation in mice by regulating the trimethylamine(TMA)/Flavin containing monooxygenase 3(FMO3)/trimethylamine N-oxide(TMAO)metabolic pathway.Methods:Sixty 4-month-old SPF grade APP/PS1 male mice were randomly divided into the model group,the Bifidobacterium Tetravaccine Tablets group,donepezil hydrochloride group,and high,medium,and low dose groups of Hei Xiaoyaosan using a random number table.The mice were orally administered continuously for 90 days.Ten male wild-type C57BL/6J mice of the same age and lineage were used as the blank control group.The open field experiment was used to detect the autonomous activity of mice,the Morris water maze test was used to test the learning and memory ability of mice,Nissl staining was used to observe the morphology of hippocampal neurons in each group of mice,enzyme-linked immunosorbent assay(ELISA)was used to detect the expression of interleukin(IL)-1β,IL-18 in mouse hippocampal tissue and tau,phosphorylation(p)-tau(Thr181),p-tau(Thr231),p-tau(Ser262),p-tau(Ser396)in mouse serum,Liquid Chromatography-Mass Spectrometry(LCMS)analysis was used to detect the level of TMAO in mouse serum,and Western blot was used to detect the expression of FMO3 in mouse liver and NOD-like receptor protein 3(NLRP3),apoptosis-associated speck-like protein(ASC),Caspase-1 proteins in hippocampus.Results:Compared with the blank group,the model group mice showed a decrease in total distance,number of times they entered the central area,and central area activity distance in the open field experiment(P<0.01).On the 3rd and 4th days of navigation experiments,the escape latency time was prolonged(P<0.01).The number of platform crossings decreased(P<0.01).Abnormal cellular structure of hippocampal neurons and blurred Nissl bodies.The hepatic cord structure is irregular,liver cells are arranged irregularly,some have nuclear dissolution,and there is a large amount of congestion in the central vein and portal area of the liver.The levels of IL-1β,IL-18 in hippocampal tissue and tau,p-tau(Thr181),p-tau(Thr231),p-tau(Ser262),p-tau(Ser396),and TMAO in serum increased(P<0.05,P<0.01).The expression of FMO3 protein increased in liver tissue(P<0.01),while the expression of NLRP3,ASC,and Caspase-1 proteins increased in hippocampus tissue(P<0.01).Compared with the model group,in the Bifidobacterium Tetravaccine Tablets group,donepezil hydrochloride group,and high-dose Hei Xiaoyaosan group,the total distance of movement,the distance of movement in the central area,and the escape latency on the 3rd and 4th days of the mice decreased(P<0.05,P<0.01),while the number of entries into the central area and the number of platform crossings increased(P<0.05,P<0.01).In each drug administration group,the damage to hippocampal neurons was improved.The expression of FMO3 protein in liver tissue and Caspase-1 protein in hippocampal tissue decreased,and the levels of IL-1β,IL-18 in mouse hippocampal tissue and tau,p-tau(Thr181),p-tau(Thr231),p-tau(Ser262),p-tau(Ser396)in mouse serum decreased(P<0.05,P<0.01).In the Bifidobacterium Tetravaccine Tablets group,donepezil hydrochloride group,and medium-and high-dose Hei Xiaoyaosan groups,the content of TMAO in mouse serum and the expression of NLRP3 and ASC proteins in hippocampal tissue decreased(P<0.05,P<0.01).Conclusion:Hei Xiaoyaosan can improve cognitive impairment in APP/PS1 mice,and its mechanism of action may be related to regulating the TMA/FMO3/TMAO metabolic pathway to inhibit neuroinflammation.