Wu Wen-Ze, Ling-Hu Ting, Zhao Yun-Hao, Zhao Wei-di, Ji Cui, Tian Jun-Sheng, Ren Yan, Qin Xue-Mei
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, Shanxi, China; The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, 030006, Shanxi, China; The Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, China.
School of Physical Education, Shanxi University, Taiyuan Shanxi, 030006, China.
J Ethnopharmacol. 2023 Jan 10;300:115702. doi: 10.1016/j.jep.2022.115702. Epub 2022 Sep 12.
In traditional Chinese medicine (TCM) theory, depression is an emotional disease, which is thought to be related to stagnation of liver qi and dysfunction of the spleen in transport. Xiaoyao San (XYS) is considered to have the effects of soothing liver-qi stagnation and invigorating the spleen. The spleen has the function to transport and transform nutrients. The liver has also termed the center of energy metabolism in the body. Therefore, exploring the antidepressant effects of XYS from the perspective of energy metabolism may reveal new findings.
Glucose catabolism is an important part of energy metabolism. In recent years, several researchers have found that XYS can exert antidepressant effects by modulating abnormalities in glucose catabolism-related metabolites. The previous research of our research group found that the hippocampus glucose catabolism was disordered in depression. However, the antidepressant potential of XYS through modulating the disorders of hippocampal glucose catabolism and the specific metabolic pathways and targets of XYS action were still unknown. The aim of this study was to address the above scientific questions.
In this research, the CUMS (chronic unpredictable mild stress) model was used as the animal model of depression. The antidepressant effect of XYS was evaluated by behavioral indicators. The specific pathways and targets of XYS modulating the disorders of glucose catabolism in the hippocampus of CUMS rats were obtained by stable isotope-resolved metabolomics. Further, the isotope tracing results were also verified by molecular biology and electron transmission electron microscopy.
The results demonstrated that XYS pretreatment could significantly improve the depressive symptoms induced by CUMS. More importantly, it was found that XYS could modulate the disorders of glucose catabolism in the hippocampus of CUMS rats. Stable isotope-resolved metabolomics and enzyme activity tests showed that Lactate dehydrogenase (LDH), Pyruvate carboxylase (PC), and Pyruvate dehydrogenase (PDH) were targets of XYS for modulating the disorders of glucose catabolism in the hippocampus of CUMS rats. The Succinate dehydrogenase (SDH) and mitochondrial respiratory chain complex V (MRCC-Ⅴ) were targets of XYS to improve abnormal mitochondrial oxidative phosphorylation in the hippocampus of CUMS rats. XYS was also found to have the ability to improve the structural damage of mitochondria and nuclei in the hippocampal caused by CUMS.
This study was to explore the antidepressant effect of XYS from the perspective of glucose catabolism based on a strategy combining stable isotope tracing, molecular biology techniques, and transmission electron microscopy. We not only obtained the specific pathways and targets of XYS to improve the disorders of glucose catabolism in the hippocampus of CUMS rats, but also revealed the specific targets of the pathways of XYS compared with VLF.
在中医理论中，抑郁症是一种情志病，被认为与肝气郁结和脾失运化有关。逍遥散（XYS）被认为具有疏肝理气、健脾的功效。脾具有运化水谷精微的功能。肝脏也被称为人体能量代谢的中心。因此，从能量代谢的角度探讨逍遥散的抗抑郁作用可能会有新的发现。
糖酵解是能量代谢的重要组成部分。近年来，一些研究人员发现逍遥散可以通过调节糖酵解相关代谢物的异常来发挥抗抑郁作用。我们研究小组之前的研究发现，抑郁症患者海马体中的糖酵解紊乱。然而，逍遥散通过调节海马体糖酵解紊乱发挥抗抑郁作用的潜力以及逍遥散作用的具体代谢途径和靶点仍不清楚。本研究的目的是解决上述科学问题。
本研究采用慢性不可预测温和应激（CUMS）模型作为抑郁症动物模型。通过行为指标评估逍遥散的抗抑郁作用。采用稳定同位素分辨代谢组学方法，获得逍遥散调节CUMS大鼠海马体糖酵解紊乱的具体途径和靶点。此外，还通过分子生物学和电子透射电子显微镜对同位素示踪结果进行了验证。
结果表明，逍遥散预处理可显著改善CUMS诱导的抑郁症状。更重要的是，发现逍遥散可以调节CUMS大鼠海马体中的糖酵解紊乱。稳定同位素分辨代谢组学和酶活性测试表明，乳酸脱氢酶（LDH）、丙酮酸羧化酶（PC）和丙酮酸脱氢酶（PDH）是逍遥散调节CUMS大鼠海马体糖酵解紊乱的靶点。琥珀酸脱氢酶（SDH）和线粒体呼吸链复合物V（MRCC-Ⅴ）是逍遥散改善CUMS大鼠海马体线粒体氧化磷酸化异常的靶点。还发现逍遥散具有改善CUMS所致海马体线粒体和细胞核结构损伤的能力。
本研究基于稳定同位素示踪、分子生物学技术和透射电子显微镜相结合的策略，从糖酵解的角度探讨逍遥散的抗抑郁作用。我们不仅获得了逍遥散改善CUMS大鼠海马体糖酵解紊乱的具体途径和靶点，还揭示了逍遥散与VLF相比在这些途径中的具体靶点。
