基于~1H NMR代谢组学技术的柴胡-白芍药对对逍遥散的贡献研究
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摘要
探究柴胡-白芍药对在逍遥散抗抑郁作用中的核心地位及作用机制。通过行为学指标观察柴胡-白芍药对、逍遥散、阴性对照(逍遥散除去柴胡、白芍)对慢性温和不可预知性抑郁(CUMS)模型大鼠行为学的影响,结果显示模型组大鼠体重、穿越格数和直立次数、糖水偏爱率均显著下降(P<0.001),强迫游泳不动时间明显延长(P<0.01)。柴胡-白芍药对有明显的抗抑郁作用,且低剂量组对大鼠穿越格数回调与逍遥散相当,高剂量组对直立次数和糖水偏爱率回调与逍遥散相当;高、低剂量组对不动时间回调均优于逍遥散。动物实验获得山西大学伦理委员会的批准。代谢组学结果提示,与抑郁症相关的15种生物标志物中,其中逍遥散回调12种,药对回调8种,阴性对照仅回调6种。通过代谢通路分析,共聚焦了4条抑郁症相关代谢通路,药对和逍遥散通过4条相同的代谢通路发挥抗抑郁作用,阴性对照仅通过其中3条通路发挥作用。综上,从行为学、代谢组学和通路分析揭示了柴胡-白芍药对在逍遥散抗抑郁中发挥重要作用。
This study explores the antidepressant mechanism of Radix Bupleuri-Radix Paeoniae Alba herb pair and the core role in Xiaoyaosan. The behavioral indicators were used to observe the effects of herb pair,Xiaoyaosan, and a negative control(Xiaoyaosan remove Radix Bupleuri-Radix Paeoniae Alba) on CUMS rats.The body weight, number of crossing and rearing, sugar preference rate were significantly decreased(P<0.001)and the immobility time of forced swimming test was significantly prolonged(P<0.01) in the model group. Radix Bupleuri-Radix Paeoniae Alba herb pair has significant antidepressant effect, with the number of crossing in low dose group similar to Xiaoyaosan, while the number of rearing and the sucrose preference rate in high dose group are equivalent to Xiaoyaosan, and the immobility time in high and low-doses group are better than Xiaoyaosan.Animal experimentation was approved according to the Committee on the Ethics of Animal Experiments of Shanxi University. Metabonomics results showed 15 biomarkers related to depression, whereas administering Xiaoyaosan or the herb pair can ameliorate 12 or 8 metabolites respectively, compared to the negative control, which can only ameliorate 6 metabolites. The metabolic pathway analysis showed 5 depression-related pathways. The herb pair and Xiaoyaosan exerted antidepressant effects through common 4 metabolic pathways, while the negative control only exerted effects through 3. In summary, behavioral, metabolomics and metabolic pathway analysis revealed that Radix Bupleuri-Radix Paeoniae Alba plays an important role in the biological effect of Xiaoyaosan.
This study explores the antidepressant mechanism of Radix Bupleuri-Radix Paeoniae Alba herb pair and the core role in Xiaoyaosan. The behavioral indicators were used to observe the effects of herb pair,Xiaoyaosan, and a negative control(Xiaoyaosan remove Radix Bupleuri-Radix Paeoniae Alba) on CUMS rats.The body weight, number of crossing and rearing, sugar preference rate were significantly decreased(P<0.001)and the immobility time of forced swimming test was significantly prolonged(P<0.01) in the model group. Radix Bupleuri-Radix Paeoniae Alba herb pair has significant antidepressant effect, with the number of crossing in low dose group similar to Xiaoyaosan, while the number of rearing and the sucrose preference rate in high dose group are equivalent to Xiaoyaosan, and the immobility time in high and low-doses group are better than Xiaoyaosan.Animal experimentation was approved according to the Committee on the Ethics of Animal Experiments of Shanxi University. Metabonomics results showed 15 biomarkers related to depression, whereas administering Xiaoyaosan or the herb pair can ameliorate 12 or 8 metabolites respectively, compared to the negative control, which can only ameliorate 6 metabolites. The metabolic pathway analysis showed 5 depression-related pathways. The herb pair and Xiaoyaosan exerted antidepressant effects through common 4 metabolic pathways, while the negative control only exerted effects through 3. In summary, behavioral, metabolomics and metabolic pathway analysis revealed that Radix Bupleuri-Radix Paeoniae Alba plays an important role in the biological effect of Xiaoyaosan.
引文
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[17]Chen SL,Chen XD.Clinical application of combined use of Radix Bupleuerl and Radix Paeoniae Alba[J].Shanghai J Tradit Chin Med(上海中医药杂志),2007,41:71-74.
[18]Li YY,Man SL,Li J,et al.The antitumor effect of formosanin Con HepG2 cell as revealed by1H NMR based metabolic profiling[J].Chem-Biol Interact,2014,220:193-199.
[19]Cui JJ,Liu YT,Hu YH,et al.NMR-based metabonomics and correlation analysis reveal potential biomarkers associated with chronic atrophic gastritis[J].J Pharm Biomed,2017,132:77-86.
[20]Jia HM,Feng YF,Liu YT,et al.Integration of1H NMR and UPLC-Q-TOF/MS for a comprehensive urinary metabonomics study on a rat model of depression induced by chronic unpredictable mild stress[J].PLoS One,2013,8:e63624.
[21]Liu XJ,Zhou YZ,Li ZF,et al.Anti-depressant effects of Xiaoyaosan on rat model of chronic unpredictable mild stress:a plasma metabonomics study based on NMR spectroscopy[J].JPharm Pharmacol,2012,64:578-588.
[22]Mohan MA,Gangurde SU,Kadam VR.Protective effect of Solanum torvum on monosodium glutamate-induced neurotoxicity in mice[J].Indian J Nat Prod Resour,2017,8:351-359.
[23]Yao WB,Yang H.Biochemistry(生物化学)[M].Beijing:People's Medical Publishing House,2011:289-299.
[24]Yao WB,Yang H.Biochemistry(生物化学)[M].Beijing:People's Medical Publishing House,2011:218-230.
[2]Wang Y,Fan R,Huang X.Meta-analysis of the clinical effectiveness of traditional Chinese medicine formula Chaihu-ShuganSan in depression[J].J Ethnopharmacol,2012,141:571-577.
[3]Wang YT,Tan QR,Sun LL,et al.Possible therapeutic effect of a traditional Chinese medicine,sinisan,on chronic restraint stress related disorders[J].Neurosci Lett,2009,449:215-219.
[4]Liu JL,Yang L,Cui J,et al.Preliminary study on serum pharmacochemisty of petroleum ether fraction in ethanol extract from Xiaoyao Powder based on UPLC-PDA[J].Chin Tradit Herb Drugs(中草药),2013,44:2816-2822.
[5]Wang Y,Gao SM,Li R,et al.Antidepressant-like effects of the Radix Bupleuri and Radix Paeoniae Alba drug pair[J].Neurosci Lett,2016,633:14-20.
[6]He J,Gao XX,Tian JS,et al.Analysis on chemical constituents in Bupleuri Radix and Paeoniae Radix Alba by UPLC-MS and their contribution to Xiaoyao powder[J].J Shanxi Med Univ(山西医科大学学报),2018,49:375-382.
[7]Puchades-Carrasco L,Pineda-Lucena A.Metabolomics in pharmaceutical research and development[J].Curr Opin Biotechnol,2015,35:73-77.
[8]Yang YZ,Deng Y,Yang XJ,et al.Application of metabonomics in TCM research[J].Chin J Inf Tradit Chin Med(中国中医药信息杂志),2018,25:132-135.
[9]Tong JH,Wang YX,Sun H,et al.Study on the pharmacodynamic differences between Hangmaidong and Chuangmaidong based on metabonomics[J].Acta Pharm Sin(药学学报),2014,49:451-1456.
[10]Jiao ML,Li ZY,Zhang FS,et al.Comparison between Astragalus membranaceus var.mongholicus and Hedysarum polybotrys based on ITS sequences and metabolomics[J].Acta Pharm Sin(药学学报),2015,50:1625-1631.
[11]Willner P.Validity,reliability and utility of the chronic mild stress model of depression:A 10-year review and evaluation[J].Psychopharmacology,1997,134:319-329.
[12]Tian JS,Shi BY,Xiang H,et al.1H-NMR-based metabonomic studies on the anti-depressant effect of genipin in the chronic unpredictable mild stress rat model[J].PLoS One,2013,8:e75721.
[13]Zhang T,Zhao F,Zhang X,et al.Antidepressant effect of Compound Chaigui prescription and its mechanism of regulating5-HT metabolic pathway[J].Chin Tradit Herb Drugs(中草药),2018,49:1338-1344.
[14]Wu S,An SC,Chen HL,et al.Orbital frontal cortex D1 dopamine receptor modulate glutamate and NMDA receptor in depression induced by chronic unpredictable mild stress[J].Acta Psychol Sin(心理学报),2014,46:69-78.
[15]Shi HS,Zhu WL,Liu JF,et al.PI3K/Akt signaling pathway in the basolateral amygdala mediates the rapid antidepressant-like effects of trefoil factor 3[J].Neuropsychopharmacol,2012,37:2671-2683.
[16]Zhao FF,Gao L,Qin XM,et al.The intervention effect of licorice in d-galactose induced aging rats by regulating the taurine metabolic pathway[J].Food Funct,2018,9:4814-4821.
[17]Chen SL,Chen XD.Clinical application of combined use of Radix Bupleuerl and Radix Paeoniae Alba[J].Shanghai J Tradit Chin Med(上海中医药杂志),2007,41:71-74.
[18]Li YY,Man SL,Li J,et al.The antitumor effect of formosanin Con HepG2 cell as revealed by1H NMR based metabolic profiling[J].Chem-Biol Interact,2014,220:193-199.
[19]Cui JJ,Liu YT,Hu YH,et al.NMR-based metabonomics and correlation analysis reveal potential biomarkers associated with chronic atrophic gastritis[J].J Pharm Biomed,2017,132:77-86.
[20]Jia HM,Feng YF,Liu YT,et al.Integration of1H NMR and UPLC-Q-TOF/MS for a comprehensive urinary metabonomics study on a rat model of depression induced by chronic unpredictable mild stress[J].PLoS One,2013,8:e63624.
[21]Liu XJ,Zhou YZ,Li ZF,et al.Anti-depressant effects of Xiaoyaosan on rat model of chronic unpredictable mild stress:a plasma metabonomics study based on NMR spectroscopy[J].JPharm Pharmacol,2012,64:578-588.
[22]Mohan MA,Gangurde SU,Kadam VR.Protective effect of Solanum torvum on monosodium glutamate-induced neurotoxicity in mice[J].Indian J Nat Prod Resour,2017,8:351-359.
[23]Yao WB,Yang H.Biochemistry(生物化学)[M].Beijing:People's Medical Publishing House,2011:289-299.
[24]Yao WB,Yang H.Biochemistry(生物化学)[M].Beijing:People's Medical Publishing House,2011:218-230.
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