背景:逍遥散(XYS),一种具有悠久临床使用历史的著名中药处方,可缓解各种抑郁症状,由柴胡(柴胡。),当归(当归(Oliv。)Diels),白芍。),白术(白术。),Poria(Poriacocos(Schw.)狼),甘草(甘草。),薄荷草(薄荷花序。),和Zin-giberisRecens(ZingiberofficinaleRosc。).
目的:我们旨在表征两种脑代谢产物的多样性和变异,即水性和亲脂性代谢物,全面了解抑郁症样行为的代谢过程,并揭示XYS类抗抑郁作用的机制。
方法:我们首先建立了CUMS(慢性不可预测的轻度压力)诱导的抑郁样行为模型。然后,我们通过两相提取方法提取了大鼠大脑的水性和亲脂性代谢物,随后通过1H核磁共振(NMR)的两个差异序列进行表征。多变量分析包括主成分分析(PCA)和正交偏最小二乘判别分析(OPLS-DA)。
结果:PCA的代谢谱分析表明XYS显著逆转了CUMS引起的代谢扰动。OPLS-DA显示总共15种代谢物,包括6种亲脂性代谢物和9种水性代谢物被筛选为参与CUMS诱导的抑郁样行为的潜在生物标志物。最重要的是,5个途径包括(1)D-谷氨酰胺和D-谷氨酸代谢,(2)缬氨酸,亮氨酸和异亮氨酸的生物合成,(3)丙氨酸,天冬氨酸和谷氨酸代谢,(4)牛磺酸和亚牛磺酸的代谢以及(5)精氨酸和脯氨酸的代谢被认为是与CUMS诱导的抑郁样行为过程相关的受影响最大的途径。值得注意的是,XYS将5种水性和4种亲脂性代谢物的异常显著逆转为正常,表明XYS协同介导了多种途径的异常(1),(3),(4)和(5)。
结论:这是首次从脑代谢物的角度研究XYS的抗抑郁样作用和潜在机制的报告。在广义上,这项研究为评估中药(TCM)的疗效带来了新颖而有价值的见解,为了解释机制,为临床上进一步研究治疗机制提供理论依据。
BACKGROUND: Xiaoyaosan (XYS), a famous TCM prescription with a long history of clinical use for relieving a wide variety of depression symptoms, consists of Radix Bupleuri (Bupleurum chinense DC.), Radix Angelicae Sinensis (Angelica sinensis (Oliv.) Diels), Radix PaeoniaeAlba (Paeonia lactiflora Pall.), Rhizoma Atractylodis Macrocepha lae (Atractylodes macrocephala Koidz.), Poria (Poria cocos (Schw.)Wolf), Radix Glycyrrhizae (Glycyrrhiza uralensis Fisch.), Herba Menthae Haplocalycis (Mentha haplocalyx Briq.), and Rhizoma Zin-giberis Recens (Zingiber officinale Rosc.).
OBJECTIVE: We aimed to characterize the diversity and variation of two kinds metabolites of brain, i.e. aqueous and lipophilic metabolites, gaining comprehensive insights into the metabolic processes of depression-like behavior, and to reveal the mechanisms of antidepressant-like effects of XYS.
METHODS: We first established a CUMS (Chronic Unpredictable Mild Stress)-induced depression-like behavior model. We then extracted both aqueous and lipophilic metabolites of rat brains by a two-phase extraction method, which were subsequently characterized by two differential sequences of 1H nuclear magnetic resonance (NMR). Multivariate analysis including Principal Components Analysis (PCA) and Orthogonal Partial Least Squares-Discriminate Analysis (OPLS-DA) was applied.
RESULTS: Metabolic profiling by PCA indicated that XYS significantly reversed the metabolic perturbation caused by CUMS. OPLS-DA showed a total of 15 metabolites including 6 lipophilic and 9 aqueous metabolites was screened as potential biomarkers involved in CUMS-induced depression-like behavior. On top of this, five pathways including (1)D-glutamine and D-glutamate metabolism, (2) valine, leucine and isoleucine biosynthesis, (3) alanine, aspartate and glutamate metabolism, (4) taurine and hypotaurine metabolism and (5) arginine and proline metabolism were recognized as the most influenced pathways associated with the process of CUMS-induced depression-like behavior. Notably, XYS significantly reversed abnormality of 5 aqueous and 4 lipophilic metabolites to normal, suggesting that XYS synergistically mediated abnormalities of multiple pathways (1), (3), (4) and (5).
CONCLUSIONS: It is the first report to investigate the antidepressant-like effects and underlying mechanisms of XYS from the perspective of brain metabolites. In a broad sense, this
study brings novel and valuable insights to evaluate the efficacy of traditional Chinese medicine (TCM), to interpret mechanisms, and to provide the theoretical basis for further research on therapeutic mechanisms in clinical practice.