基于液质联用代谢组学技术的酸枣仁汤抗抑郁作用机制研究  

UPLC-Q-Orbitrap-MS based metabolomics and analysis of the effect of Suanzaoren Decoction on serum of chronic unpredictable mild stress depression rats

作　　者：吴江 韩瑞 赵妮 褚迎新 张荫杰 秦雪梅[1] 杜晨晖 闫艳[1] WU Jiang;HAN Rui;ZHAO Ni;CHU Ying-xin;ZHANG Yin-jie;QIN Xue-mei;DU Chen-hui;YAN Yan(Modern Research Center for Traditional Chinese Medicine,Shanxi University,Taiyuan 030006,China;Institute of Pharmaceutical&Food Engineering,Shanxi University of Chinese Medicine,Taiyuan 030619,China)

机构地区：[1]山西大学中医药现代研究中心,山西太原030006 [2]山西中医药大学中药与食品工程学院,山西太原030619

出　　处：《药学学报》2023年第7期1952-1962,共11页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金青年基金资助项目(81603289,81603251);山西省基础研究计划项目(20210302123470);山西省卫生健康委“十大晋药”中药材质量标准规范制定和综合利用研究项目(Zyczl2020007);山西省科学技术厅中央引导地方科技发展资金项目(YDZJSX2021C025);山西省科学技术厅-地产中药功效物质研究与利用山西省重点实验室项目(201605D111004);山西省研究生创新项目(2022Y163).

摘　　要：利用超高效液相色谱串联四极杆-静电场轨道阱高分辨质谱(UPLC-Q-Orbitrap-MS)代谢组学技术分析酸枣仁汤(Suanzaoren decoction,SZRD)对慢性不可预知温和应激(chronic unpredictable mild stress,CUMS)抑郁模型大鼠血清内源性代谢物代谢紊乱的调控作用,明确酸枣仁汤发挥抗抑郁作用的代谢调控途径。将大鼠随机分为正常对照组、模型组、阳性药文拉法辛组以及酸枣仁汤高(24 g·kg^(-1))、低剂量(12 g·kg^(-1))组。分别对大鼠实施热刺激、冰水游泳、超声刺激、夹尾、昼夜颠倒、足底电击等刺激,复制CUMS模型,造模同时给予药物,持续28天后,观察各组大鼠行为学指标并收集大鼠海马组织以及血清样本。与CUMS模型组大鼠相比,酸枣仁汤低剂量和高剂量组能显著降低强迫游泳不动时间(P<0.001,P<0.001)、提高糖水偏爱率(P<0.01,P<0.05)、旷场实验穿越格数(P<0.05,P<0.01)和直立次数(P<0.05,P<0.01),并能明显降低血清中IL-6、IL-1β以及TNF-α等炎性因子水平而发挥抗抑郁作用。能显著改善CUMS模型组大鼠抑郁样行为。共鉴定与指认出血清中与抑郁相关的21个差异代谢物,酸枣仁汤低剂量组能显著回调8种,酸枣仁汤高剂量组能显著回调其中11种。代谢通路分析显示丙氨酸、天冬氨酸和谷氨酸代谢、色氨酸代谢通路和花生四烯酸代谢是酸枣仁汤发挥抗抑郁作用的主要代谢途径。本研究为扩大酸枣仁汤临床适应证提供了科学依据。本实验获得山西大学动物伦理委员会批准(批准号:SXULL2020028)。A UPLC-Q-Orbitrap-MS based metabolomic approach combined with biochemical assay and histopathological inspection were employed to study the intervention effects of Suanzaoren Decoction(SZRD)on chronic unpredictable mild stress(CUMS)depression rats,and to clarify the metabolic regulation pathway of SZRD.The rats were randomly divided into normal control group,CUMS model group,positive drug venlafaxine group,SZRD high(24 g·kg-1)and low(12 g·kg-1)dose groups,respectively.The CUMS model was replicated by subjecting to a variety of stimulus,such as thermal stimulation,ice water swimming,ultrasonic stimulation,tail clamping,day and night reversal,plantar electric shock and so on for rats.After oral administration of drugs for 28 days,the behavioral indexes of rats in each group were observed and the hippocampus and serum samples of rats were collected for biochemical assay and histopathological inspection.Compared with the CUMS model group,low dose and high dose SZRD groups can significantly reduce the immobility time of forced swimming(P<0.001,P<0.001),increase the sucrose preference rate(P<0.01,P<0.05),the number of crossings(P<0.05,P<0.01)and the number of uprights(P<0.05,P<0.01)in the open field test,suggesting that SZRD can significantly improve the depression-like behavior of CUMS model rats.In addition,SZRD could significantly reduce the levels of serum IL-6,IL-1βand TNF-αof CUMS model rats.A total of 21 differential metabolites in serum were identified by comparison with the data from the literature and databases.In addition,low-dose SZRD and highdose SZRD improved the 8 and 11 perturbed potential serum biomarkers that were induced by CUMS,respectively,which related to alanine,aspartic acid and glutamic acid,tryptophan and arachidonic acid metabolism.This study provides a scientific basis for expanding the clinical indications of SZRD.This experiment was approved by the Animal Ethics Committee of Shanxi University(Approval No.SXULL2020028).

关 键 词：酸枣仁汤 UPLC-Q-Orbitrap-MS 血清代谢组学 慢性不可预知温和应激抑郁 作用机制 

分 类 号：R917[医药卫生—药物分析学]