基于^(1)H-NMR代谢组学探讨柴胡-白芍药对“疏肝解郁”的代谢调控途径

Metabolic Pathways Related to Liver-soothing and Depression-relieving Effect of Bupleuri Radix-Paeoniae Radix Alba Combination:Based on ^(1)H-NMR Metabolomics

目的:利用核磁共振氢谱(1H-NMR)代谢组学技术,分析慢性不可预知温和应激(CUMS)抑郁模型大鼠肝脏内源性代谢物的变化,观察柴胡-白芍药对对此的调节作用,分析柴胡-白芍药对疏肝解郁相关的代谢通路。方法:将SD大鼠随机分为对照组、CUMS模型组、阳性药文拉法辛组和柴胡-白芍药对高(CBH)、低(CBL)剂量组。通过抑郁症的传统药效学指标(大鼠体质量、旷场测试、糖水偏爱实验及强迫游泳实验)评价柴胡-白芍药对的药效。采用1H-NMR代谢组学技术结合多元统计分析方法,分析CBH、CBL组大鼠肝脏代谢物的变化,鉴定可靠的生物标志物并进行代谢通路分析。结果:与对照组比较,模型组大鼠药效学指标均有显著变化,即体质量,旷场穿越格数、直立次数,糖水偏爱率降低(P<0.001)及强迫游泳不动时间增加(P<0.001);柴胡-白芍药对能显著改善模型组大鼠的抑郁样行为。1H-NMR代谢组学分析显示,CUMS会使大鼠体内24个代谢物和10条代谢通路紊乱,柴胡-白芍药对能显著回调其中的21个差异代谢物,对其中7条代谢通路产生影响。结论:柴胡-白芍药对能够改善CUMS抑郁模型大鼠的抑郁样症状,可能是通过调节大鼠体内氨基酸代谢和能量代谢等通路实现的。

Objective:To analyze the changes of hepatic endogenous metabolites in rats with chronic unpredictable mild stress(CUMS)-induced depression based on 1H-nuclear magnetic resonance(1H-NMR)metabolomics,observe the regulating effect of Bupleuri Radix-Paeoniae Radix Alba combination(CB),and further clarify metabolic pathways related to the liver-soothing and depression-relieving effect of the combination.Methods:Rats were randomized into five groups:blank,model,positive control(venlafaxine),high-dose CB(CBH),and low-dose CB(CBL).The conventional pharmacodynamic indicators of depression such as body weight,number of crossings and rearings in open field test,and sucrose preference rate were employed to investigate the efficacy of CB.1H-NMR was combined with multivariate statistical analysis method to analyze the changes of metabolites in rat liver upon intervention with CBL and CBH.On this basis,key differential metabolites were screened and related metabolic pathways were elucidated.Results:Pharmacodynamic indexes of the rats in the model group changed significantly as compared with those in the blank group,as evidenced by the reduction of body weight,number of crossings and rearings in open field test,and sucrose preference rate(P<0.001)and the increase in immobility time in forced swimming(P<0.001).CB can significantly improve the depression-like behaviors of rats in the model group.According to 1H-NMR metabolomics analysis,CUMS affected 24 metabolites and 10 metabolic pathways,and 21 of them can be significantly recovered by CB.Metabolic pathway analysis showed that the CB exerted antidepressant effect through 7 metabolic pathways.Conclusion:CB can alleviate the depression-like symptoms of CUMS model rats,which may be related with the metabolic pathways of amino acids and energy in rats.