Su Zhi-heng, Jia Hong-mei, Zhang Hong-wu, Feng Yu-Fei, An Lei, Zou Zhong-mei
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, P. R. China.
Mol Biosyst. 2014 Mar 4;10(3):549-61. doi: 10.1039/c3mb70377k. Epub 2014 Jan 7.
Chaihu-Shu-Gan-San (CSGS), a traditional Chinese medicine formula, has been effectively used for the treatment of depression. However, studies of its anti-depressive mechanism are challenging, due to the complex pathophysiology of depression, and complexity of CSGS with multiple constituents acting on different receptors. In the present work, metabolomic studies of biochemical changes in the hippocampus and serum of chronic variable stress (CVS)-induced depression rats after treatment with CSGS were performed using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Partial least squares-discriminate analysis indicated that the metabolic perturbation induced by CVS was reduced by treatment with CSGS. A total of twenty-six metabolites (16 from the hippocampus and 10 from serum) were considered as potential biomarkers involved in the development of depression. Among them, 11 were first reported to have potential relevance in the pathogenesis of depression, and 25 may correlate to the regulation of CSGS treatment on depression. The results combined with a previous study indicated that CSGS mediated synergistically abnormalities of the metabolic network, composed of energy metabolism, synthesis of neurotransmitters, tryptophan, phospholipids, fatty acid and bile acid metabolism, bone loss and liver detoxification, which may be helpful for understanding its mechanism of action. Furthermore, the extracellular signal-regulated kinase (ERK) signal pathway, involved in the neuronal protective mechanism of depression related to energy metabolism, was investigated by western blot analysis. The results showed that CSGS reversed disruptions of BDNF, ERK1/2 and pERK1/2 in CVS rats, which provides the first evidence that the ERK signal system may be one of the targets related to the antidepressant action of CSGS.
柴胡疏肝散（CSGS）是一种中药方剂，已被有效用于治疗抑郁症。然而，由于抑郁症复杂的病理生理学以及CSGS成分复杂，多种成分作用于不同受体，对其抗抑郁机制的研究具有挑战性。在本研究中，采用超高效液相色谱-四极杆飞行时间质谱联用技术（UPLC-QTOF-MS）对慢性可变应激（CVS）诱导的抑郁大鼠经CSGS治疗后海马和血清中的生化变化进行了代谢组学研究。偏最小二乘判别分析表明，CSGS治疗可减轻CVS诱导的代谢紊乱。共有26种代谢物（16种来自海马，10种来自血清）被认为是参与抑郁症发生发展的潜在生物标志物。其中，11种首次被报道与抑郁症发病机制具有潜在相关性，25种可能与CSGS治疗对抑郁症的调节作用相关。研究结果与先前的一项研究相结合表明，CSGS协同介导了由能量代谢、神经递质合成、色氨酸、磷脂、脂肪酸和胆汁酸代谢、骨质流失及肝脏解毒组成的代谢网络异常，这可能有助于理解其作用机制。此外，通过蛋白质免疫印迹分析研究了参与抑郁症能量代谢相关神经保护机制的细胞外信号调节激酶（ERK）信号通路。结果显示，CSGS可逆转CVS大鼠中脑源性神经营养因子（BDNF）、ERK1/2和磷酸化ERK1/2（pERK1/2）的破坏，这首次证明ERK信号系统可能是与CSGS抗抑郁作用相关的靶点之一。
