Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, PR China.
J Pharm Biomed Anal. 2011 Jun 1;55(3):533-9. doi: 10.1016/j.jpba.2011.02.013. Epub 2011 Feb 18.
Chaihu-Shu-Gan-San (CSGS), a traditional Chinese medicine (TCM) formula, has been effectively used for the treatment of depression in clinic. However, studies of its anti-depressive mechanism are challenging, accounted for the complex pathophysiology of depression, and complexity of CSGS with multiple constituents acting on different metabolic pathways. The variations of endogenous metabolites in rat model of depression after administration of CSGS may offer deeper insights into the anti-depressive effect and mechanism of CSGS. In this study, metabonomics based on ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used to profile the metabolic fingerprints of urine obtained from chronic variable stress (CVS)-induced depression model in rats with and without CSGS treatment. Through partial least squares-discriminate analysis, it was observed that metabolic perturbations induced by chronic variable stress were restored in a time-dependent pattern after treatment with CSGS. Metabolites with significant changes induced by CVS, including 3-O-methyldopa (1), pantothenic acid (2), kynurenic acid (3), xanthurenic acid (4), 2,8-dihydroxyquinoline glucuronide (5), 5-hydroxy-6-methoxyindole glucurnoide (8), l-phenylalanyl-l-hydroxyproline (9), indole-3-carboxylic acid (10), proline (11), and the unidentified metabolites (6, 2.11min_m/z 217.0940; 7, 2.11min_m/z 144.0799), were characterized as potential biomarkers involved in the pathogenesis of depression. The derivations of all those biomarkers can be regulated by CSGS treatment except indole-3-carboxylic acid (10), which suggested that the therapeutic effect of CSGS on depression may involve in regulating the dysfunctions of energy metabolism, tryptophan metabolism, bone loss and liver detoxification. This study indicated that the rapid and noninvasive urinary metabonomics approach may be a powerful tool to study the efficacy and mechanism of complex TCM prescriptions.
柴胡疏肝散（CSGS）是一种传统中药（TCM）配方，已在临床上有效用于治疗抑郁症。然而，由于抑郁症的复杂病理生理学和 CSGS 具有多种成分作用于不同代谢途径的复杂性，因此研究其抗抑郁机制具有挑战性。CSGS 给药后抑郁模型大鼠内源性代谢物的变化可能会更深入地了解 CSGS 的抗抑郁作用和机制。在这项研究中，基于超高效液相色谱-四极杆飞行时间质谱联用（UPLC-QTOF-MS）的代谢组学被用于分析 CSGS 治疗慢性可变应激（CVS）诱导的抑郁模型大鼠尿液中的代谢指纹图谱。通过偏最小二乘判别分析，观察到 CSGS 治疗后，慢性可变应激引起的代谢紊乱呈时间依赖性恢复。CVS 诱导的具有显著变化的代谢物，包括 3-O-甲氧基多巴（1）、泛酸（2）、犬尿氨酸（3）、黄尿酸（4）、2,8-二羟基喹啉葡萄糖醛酸（5）、5-羟基-6-甲氧基吲哚葡萄糖醛酸（8）、L-苯丙氨酰-L-羟脯氨酸（9）、吲哚-3-羧酸（10）、脯氨酸（11）和未鉴定的代谢物（6，2.11min_m/z 217.0940；7，2.11min_m/z 144.0799），被鉴定为参与抑郁症发病机制的潜在生物标志物。除了吲哚-3-羧酸（10）之外，所有这些生物标志物的推导都可以通过 CSGS 治疗来调节，这表明 CSGS 对抑郁症的治疗效果可能涉及调节能量代谢、色氨酸代谢、骨质流失和肝脏解毒功能的失调。本研究表明，快速、非侵入性的尿代谢组学方法可能是研究复杂 TCM 处方疗效和机制的有力工具。
