六味抗抑郁汤通过调控TLR4/MyD88/NF-κB/NLRP3通路和抑制炎症因子改善小鼠抑郁样行为的机制研究  

Liuwei Kangyiyu(六味抗抑郁)Decoction Mitigates Depression-Like Behaviors in Mice by Regulating TLR4/MyD88/NF-κB/NLRP3 Pathway and Inhibiting Inflammatory Cytokines

作　　者：徐道祥 贺君宇 石孟琼[1] 史惠敏 XU Daoxiang;HE Junyu;SHI Mengqiong;SHI Huimin(College of Basic Medical Sciences&Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy,China Three Gorges University,Yichang 443002;Wenzhou Seventh People’s Hospital,Wenzhou 325000)

机构地区：[1]三峡大学基础医学院&肿瘤微环境与免疫治疗湖北省重点实验室(三峡大学),宜昌443002 [2]温州市第七人民医院,温州325000

出　　处：《中药药理与临床》2024年第8期28-35,共8页Pharmacology and Clinics of Chinese Materia Medica

基　　金：浙江省自然科学基金项目(编号:LGF21H090002);温州市科技局项目(编号:Y20210497)。

摘　　要：目的:探讨六味抗抑郁汤对抑郁症小鼠神经细胞以及Toll样受体4(TLR4)/髓分化因子88(MyD88)/核因子kappa B(NF-κB)/NOD样受体热蛋白结构域相关蛋白3(NLRP3)信号通路的影响。方法:将雄性C57BL/6J小鼠随机分成正常对照组、慢性轻度不可预测的刺激(CUMS)模型组,六味抗抑郁汤9.62、19.24、38.48 g/kg组和氟西汀5.20 mg/kg组,每组12只。采用CUMS法制备抑郁症小鼠模型。各组分别灌胃给予相应药物,正常对照组和CUMS模型对照组给予等体积蒸馏水,1次/d,连续4 w。采用蔗糖偏好、强迫游泳、悬尾、旷场、Morris水迷宫试验检测各组小鼠行为学;检测各组小鼠血液和海马组织中炎症介质(iNOS、NO、COX-2、PGE2)和炎症因子(TNF-α、IL-1β、IL-18、IL-6、IFN-γ)含量;检查海马组织病理学变化;Real-time PCR法检测海马组织中Tlr4/Myd88/Nfkb/Nlrp3通路相关基因的表达。结果:与正常对照组比较,模型对照组小鼠糖水偏好率,水平穿越格子数、直立次数,目标象限的百分率以及穿越平台次数明显降低(P<0.01);强迫游泳和悬尾不动时间升高,游泳潜伏期明显延长,血清和海马组织中iNOS、NO、COX-2、PGE2、TNF-α、IL-1β、IL-18、IL-6、IFN-γ含量显著升高,海马神经元细胞排列紊乱和胞体空泡增多,炎性细胞浸润,海马组织中Tlr4、Myd88、Irak1、Irak4、Tak1、Traf6、Nfkb、Nlrp3、Asc、Capsase1、Nek7、Txnip、Gsdmd、Il1b、Il18 mRNA表达上调(P<0.05或P<0.01);与模型对照组比较,六味抗抑郁汤可明显升高CUMS模型小鼠糖水偏好率,水平穿越格子数、直立次数,目标象限的百分率以及穿越平台次数,降低强迫游泳和悬尾不动时间,缩短游泳潜伏期,可显著减低CUMS模型小鼠血清和海马组织中iNOS、NO、COX-2、PGE2、TNF-α、IL-1β、IL-18、IL-6、IFN-γ含量,减少海马神经元细胞排列紊乱和胞体空泡,减轻炎性细胞浸润,显著下调小鼠海马组织中Tlr4、Myd88、Irak1、Irak4、Tak1、Traf6�Objective:To explore the effects of Liuwei Kangyiyu(六味抗抑郁)Decoction on the neurons and Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor-κB(NF-κB)/NOD-like receptor protein 3(NLRP3)signaling pathway in depressed mice.Methods:Male C57BL/6J mice were randomized into a blank control group,a model(chronic mild unpredictable stress,CUMS)group,Liuwei Kangyiyu Decoction(9.62,19.24,and 38.48 g/kg)groups,and a fluoxetine(5.20 mg/kg)group,with 12 mice in each group.The CUMS method was employed to establish the mouse model of depression.Each group was administrated with the corresponding drug by gavage,while the normal control group and the model group were administrated with equal volume of distilled water once a day for 4 consecutive weeks.The sucrose preference,forced swimming,tail suspension,open field,and Morris water maze tests were carried out to examine the behaviors of mice.The levels of inflammatory mediators[inducible nitric oxide synthase(iNOS),nitric oxide(NO),cyclooxygenase-2(COX-2),and prostaglandin E_2(PGE_2)]and cytokines[tumor necrosis factor(TNF)-α,interleukin(IL)-1β,IL-18,IL-6,and interferon(IFN)-γ]in blood and hippocampal tissue were determined.The histopathological changes of the hippocampus were examined.Real-time PCR was employed to measure the relative mRNA levels of genes in the TLR4/MyD88/NF-κB/NLRP3 signaling pathway in the hippocampal tissue.Results:Compared with the normal control group,the model group showed reduced sucrose consumption,number of crossings,number of rearings,percentage in target quadrants,and number of platform crossings,increased duration of forced swimming and tail suspension,and prolonged swimming latency.The levels of iNOS,NO,COX-2,PGE_2,TNF-α,IL-1β,IL-18,IL-6,and IFN-γin blood and hippocampal tissue were significantly increased in the model group.In addition,the modeling led to disarrangement of hippocampal neurons,increased number of vacuoles in the cells,infiltration of inflammatory cells,and up-regulated mRNA levels of

关 键 词：六味抗抑郁汤 抑郁症 炎性激活 Toll样受体4/髓分化因子88/核因子kappa B/NOD样受体热蛋白结构域相关蛋白3信号通路 

分 类 号：R285.5[医药卫生—中药学]