中国中药杂志

2021, v.46(24) 6511-6519

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基于脑内海马区SIRT1表达的变化研究交泰丸对CUMS抑郁模型小鼠的影响
Effects of Jiaotai Pills on CUMS-induced depression model in mice based on changes of SIRT1 expression in hippocampus

戴国梁;杨欣怡;陈闪闪;王一清;刘美琛;曹阳;李斐然;马程遥;居文政;
DAI Guo-liang;YANG Xin-yi;CHEN Shan-shan;WANG Yi-qing;LIU Mei-chen;CAO Yang;LI Fei-ran;MA Cheng-yao;JU Wen-zheng;Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine;

摘要(Abstract):

研究交泰丸对慢性不可预知温和刺激(chronic unpredictable mild stress, CUMS)模型小鼠的抗抑郁作用及机制。建立CUMS抑郁模型小鼠,通过糖水偏好实验、旷场实验、悬尾实验及强迫游泳实验评价小鼠的抑郁行为;运用分子对接技术探究交泰丸中主要活性成分与SIRT1相互作用模式;免疫组织化学染色法检测小鼠海马区SIRT1水平;蛋白印迹法检测小鼠海马区SIRT1、p-NF-κB p65、NF-κB p65及FoxO1的蛋白表达水平;酶联免疫分析试剂盒检测小鼠海马及血清中白细胞介素(interleukin, IL)-1β、IL-6、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)及脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)水平;生化试剂盒检测小鼠海马及血清中超氧化物歧化酶(superoxide dismutase, SOD)活性及丙二醛(malondialdehyde, MDA)、谷胱甘肽(glutathione, GSH)水平;液相色谱-质谱法(liquid chromatography/tandem mass spectrometry, LC-MS/MS)检测小鼠海马及血清中多巴胺(dopamine, DA)、5-羟色胺(5-hydroxytryptamine, 5-HT)及去甲肾上腺素(norepinephrine, NE)水平。结果显示,模型组小鼠糖水偏好率、运动距离及穿越中心次数显著降低(P<0.01),悬尾不动时间和游泳不动时间显著增加(P<0.01),分子对接结果显示交泰丸中6个主要活性成分与SIRT1间均存在较好的结合效应,海马区SIRT1表达水平显著降低(P<0.01),海马区p-NF-κB p65/NF-κB p65及FoxO1的水平显著增加(P<0.01),海马区和血清中IL-1β、IL-6、TNF-α及MDA水平显著增加(P<0.01),海马区和血清中SOD活性及GSH、DA、5-HT、NE和BDNF水平显著降低(P<0.01)。交泰丸高剂量组的治疗显著增加模型小鼠糖水偏好率、运动距离和穿越中心次数(P<0.05),显著降低悬尾不动时间和游泳不动时间(P<0.01),增加海马区SIRT1表达水平(P<0.01),降低海马和血清中IL-1β、IL-6、TNF-α及MDA水平(P<0.01),提高海马和血清中SOD活性及GSH、DA、5-HT、NE和BDNF水平(P<0.05,P<0.01)。研究结果表明,交泰丸可改善CUMS模型小鼠的抑郁行为,其机制与上调小鼠海马区SIRT1而发挥抗炎和抗氧化应激作用有关。
The present study investigated the effects and mechanisms of Jiaotai Pills on depressed mice induced by chronic unpredictable mild stress(CUMS). The CUMS-induced depression model mice were established and the depression behaviors of mice were evaluated by sucrose preference test, open field test, tail suspension test, and forced swimming test. Molecular docking was employed to simulate the interaction of six main active ingredients in Jiaotai Pills with SIRT1. Immunohistochemical staining was used to detect the level of SIRT1 in the hippocampus of mice. Western blot was used to detect the protein expression levels of SIRT1, p-NF-κB p65, NF-κB p65, and FoxO1 in the hippocampus of mice. Enzyme-linked immunosorbent assay(ELISA) kits were used to detect the levels of interleukin(IL)-1β, IL-6, tumor necrosis factor-α(TNF-α), and brain-derived neurotrophic factor(BDNF) in the hippocampus and serum of mice. Biochemical kits were used to detect superoxide dismutase(SOD) activity and malondialdehyde(MDA) and glutathione(GSH) levels in the hippocampus and serum of mice. Liquid chromatography-tandem mass spectrometry(LC-MS/MS) was used to detect the levels of dopamine(DA), 5-hydroxytryptamine(5-HT), and norepinephrine(NE) in the hippocampus and serum of mice. The results showed that the sucrose preference rate, movement distance, and the number of crossing centers were reduced in the model group(P<0.01), and the tail suspension time and swimming immobility time were increased(P<0.01). Molecular docking results indicated good binding of six main active ingredients in Jiaotai Pills to SIRT1. In the hippocampus, the expression level of SIRT1 was reduced(P<0.01), and the levels of p-NF-κB p65/NF-κB p65 and FoxO1 were increased(P<0.01). In the hippocampus and serum, the levels of IL-1β, IL-6, TNF-α, and MDA were increased(P<0.01), and the activity of SOD and the levels of GSH, DA, 5-HT, NE, and BDNF were reduced(P<0.01). The treatment with high-dose Jiaotai Pills increased the sucrose preference rate, movement distance, and the number of crossing centers(P<0.05), reduced tail suspension time and swimming immobility time(P<0.01), elevated hippocampal SIRT1 expression level(P<0.01), decreased hippocampal and serum IL-1β, IL-6, TNF-α, and MDA levels(P<0.01), potentiated SOD activity, and up-regulated GSH, DA, 5-HT, NE, and BDNF levels in the hippocampus and serum(P<0.05, P<0.01) in model mice. In conclusion, the results showed that Jiaotai Pills could improve the depression behaviors of model mice with CUMS-induced depression, and the underlying mechanism was related to the up-regulation of SIRT1 in the hippocampus of mice to exert anti-inflammatory and anti-oxidative stress effects.

关键词(KeyWords): 交泰丸;抑郁;SIRT1;炎症;氧化应激
Jiaotai Pills;depression;SIRT1;inflammation;oxidative stress

Abstract:

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基金项目(Foundation): 江苏省中医药领军人才项目(SLJ0208);; 江苏省自然科学基金面上项目(BK20211394)

作者(Author): 戴国梁;杨欣怡;陈闪闪;王一清;刘美琛;曹阳;李斐然;马程遥;居文政;
DAI Guo-liang;YANG Xin-yi;CHEN Shan-shan;WANG Yi-qing;LIU Mei-chen;CAO Yang;LI Fei-ran;MA Cheng-yao;JU Wen-zheng;Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine;

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