基于血清代谢组学技术探讨桂枝茯苓胶囊及其主要成分治疗原发性痛经的作用机制  

Study on the therapeutic mechanism of Guizhi Fuling Capsules and its main components for treatment of primary dysmenorrhea syndrome by serum metabolomics

作　　者：段昆 高霞[2,3] 耿婷[2,3] 陈夏霖 曹亮[2,3] 肖伟[2,3] 王振中[2,3] DUAN Kun;GAO Xia;GENG Ting;CHEN Xia-lin;CAO Liang;XIAO Wei;WANG Zhen-zhong(School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China;Jiangsu Kanion Pharmaceutical Co.,Ltd.,Lianyungang 222001,China;State Key Laboratory of New-tech for Chinese)

机构地区：[1]南京中医药大学药学院,南京210023 [2]江苏康缘药业股份有限公司,连云港222001 [3]中药制药过程新技术国家重点实验室,连云港222001

出　　处：《中国新药杂志》2020年第18期2066-2074,共9页Chinese Journal of New Drugs

基　　金：国家“重大新药创制”科技重大专项资助项目(2018ZX09201010-004):基于功效成分群的中药口服固体制剂先进制药与信息化技术融合示范应用。

摘　　要：目的:采用血清代谢组学技术从内源性代谢物的角度研究桂枝茯苓胶囊及其主要成分(芍药苷、丹皮酚、苦杏仁苷)治疗原发性痛经的作用机制。方法:将36只SD雌性大鼠随机分为正常组、模型组、桂枝茯苓组、芍药苷组、丹皮酚组、苦杏仁苷组,每组6只。注射苯甲酸雌二醇(连续10 d)和缩宫素(d 10)制备大鼠原发性痛经模型,通过扭体反应和子宫药效学指标评价药物的疗效;同时应用UPLC-Q-TOF-MS/MS技术,结合多元变量分析和数据库检索,对不同组别大鼠血清中内源性代谢物进行分析,筛选鉴定出潜在的差异代谢物;并通过Metabo Analyst软件进行代谢通路分析。结果:桂枝茯苓胶囊、芍药苷和丹皮酚均能较好地抑制模型大鼠扭体反应,并能降低模型大鼠子宫中一氧化氮(NO)和丙二醛(MDA)含量。通过主成分分析(PCA)和偏最小二乘法-判别分析(PLS-DA)发现正常大鼠和模型大鼠的代谢轮廓发生明显变化,共鉴定出12种与原发性痛经相关的差异代谢物,涉及的潜在靶标代谢通路(Impact>0.1)包括亚油酸代谢,苯丙氨酸、酪氨酸和色氨酸的生物合成,苯丙氨酸代谢,花生四烯酸代谢以及色氨酸代谢。经桂枝茯苓胶囊、芍药苷和丹皮酚干预后,5条紊乱的代谢通路均有回调趋势;苦杏仁苷对受扰动最大的亚油酸代谢无回调作用。结论:桂枝茯苓胶囊及其主要成分对原发性痛经模型大鼠的代谢紊乱均具有一定调节作用,其中芍药苷和丹皮酚发挥主要作用,与药效学结果一致,其作用机制主要与脂质代谢、氨基酸代谢有关。Objective:To study the mechanism of Guizhi Fuling Capsules and its principal components(paeoniflorin,paeonol and amygdalin)for treating primary dysmenorrhea syndrome from the aspect of endogenous metabolites by metabolomics.Methods:Thirty-six SD rats were randomly divided into six groups,including blank group,model group,Guizhi Fuling group,paeoniflorin group,paeonol group and amygdalin group(n=6).Rats were injected with estradiol benzoate(for 10 d)and oxytocin(on the 10th day)to set the model of primary dysmenorrhea except those in the blank group.The efficacy of the drug was evaluated by twisting reaction of rats and the MDA&NO contents in rat uterus tissues.Meanwhile,UPLC-Q-TOF-MS/MS combined with multivariate analysis and database search was used to analyzed the endogenous metabolites in rat serum from different groups and discover differential metabolites.Besides,metabolites were analyzed by Metabo Analyst software for possible metabolic pathways.Results:Guizhi Fuling Capsules,paeoniflorin and paeonol were able to well inhibit the writhing reaction and reduce NO and MDA levels in the uterus of rats.Distinct change of metabolites between the blank group and the model group could be seen by PCA and PLS-DA.What's more,12 potential differential metabolites of primary dysmenorrhea were identified.Involved potential metabolic pathways included linoleic acid metabolism,phenylalanine,tyrosine and tryptophan biosynthesis,phenylalanine metabolism,arachidonic acid metabolism,and tryptophan metabolism.Guizhi Fuling Capsules,paeoniflorin and paeonol had a certain callback effect on the five metabolic pathways in primary dysmenorrhea rats,while amygdalin had no effect on linoleic acid metabolism.Conclusion:Guizhi Fuling Capsules and its principal components(paeoniflorin,paeonol and amygdalin)have a certain callback effect on the metabolic disorder of the primary dysmenorrhea rats.Paeoniflorin and paeonol play a major role,which is consistent with the pharmacodynamics results.Their therapeutic mechanism is mainly related t

关 键 词：桂枝茯苓胶囊 代谢组学 原发性痛经 UPLC-Q-TOF-MS/MS 

分 类 号：R975.5[医药卫生—药品]