Huang Dehua, Lv Jiale, Gong Wenxia, Tian Junsheng, Gao Xiaoxia, Qin Xuemei, Du Guanhua, Zhou Yuzhi
Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, No. 92, Wucheng Road, Taiyuan, Shanxi 030006, P. R. China.
Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Shanxi University, No. 92, Wucheng Road, Taiyuan, Shanxi 030006, P. R. China.
ACS Chem Neurosci. 2025 May 7;16(9):1749-1766. doi: 10.1021/acschemneuro.4c00804. Epub 2025 Apr 10.
Depression is a complex mental disorder. Studies have shown that purine metabolism disorders in depression and regulation of purine metabolites and related purinergic receptors may be an effective way to alleviate depression. Chaigui granules (CG) are a Chinese medicine prescription with antidepressant effects. Its antidepressant effect has been shown to be related to the improvement of purine metabolism disorders in depression. In this study, exogenous purine metabolite adenosine supplementation and adenosine A1 receptor antagonist (DPCPX) were employed to investigate the potential of Chaigui granules to exert an antidepressant effect by examining the behavioral indices of CUMS rats. The aim of this study was to determine whether the antidepressant effect of Chaigui granules is mediated by A1R receptors using DPCPX, an A1R receptor antagonist. Nontargeted metabolomic analysis was employed to compare and analyze the alterations in the metabolic profile of plasma and peripheral blood mononuclear cells (PBMCs) in each experimental group. Subsequently, combining the results from the metabolomics profile, targeted metabolomics was employed to identify key metabolites for purine metabolism. The objective was to investigate the effects of Chaigui granules, exogenous adenosine supplementation, and DPCPX on purine metabolism in depressed rats. Finally, the relevant signal pathways were validated by molecular biological means. The results of the depression-like behavior indicate that the antidepressant efficacy of Chaigui granules was associated with the modulation of adenosine and adenosine A1 receptor. Metabolomic analysis demonstrated that the Chaigui granule and adenosine exerted a pronounced regulatory effect on purine metabolism, and the regulatory effect on peripheral blood mononuclear cells (PBMCs) was markedly superior to that observed in plasma. In addition, targeted quantitative analysis showed that all eight purine metabolites were reversed after the administration of Chaigui granules and adenosine. Concurrently, the administration of an adenosine A1 receptor antagonist may serve to mitigate the regulatory impact of Chaigui granules on purine metabolites. Finally, the molecular biological results indicate that the antidepressant effect of Chaigui granules may be mediated by the A1R receptor, and it can play an antidepressant role by regulating the CAMP-PKA-CREB-BDNF pathway.
抑郁症是一种复杂的精神障碍。研究表明，抑郁症中的嘌呤代谢紊乱以及嘌呤代谢产物和相关嘌呤能受体的调节可能是缓解抑郁症的有效途径。柴桂颗粒（CG）是一种具有抗抑郁作用的中药方剂。其抗抑郁作用已被证明与改善抑郁症中的嘌呤代谢紊乱有关。在本研究中，通过补充外源性嘌呤代谢产物腺苷和腺苷A1受体拮抗剂（DPCPX），并检测慢性不可预知温和应激（CUMS）大鼠的行为指标，来研究柴桂颗粒发挥抗抑郁作用的潜力。本研究的目的是使用A1R受体拮抗剂DPCPX来确定柴桂颗粒的抗抑郁作用是否由A1R受体介导。采用非靶向代谢组学分析对各实验组血浆和外周血单个核细胞（PBMC）的代谢谱变化进行比较和分析。随后，结合代谢组学分析结果，采用靶向代谢组学来鉴定嘌呤代谢的关键代谢产物。目的是研究柴桂颗粒、外源性腺苷补充剂和DPCPX对抑郁大鼠嘌呤代谢的影响。最后，通过分子生物学手段验证相关信号通路。抑郁样行为的结果表明，柴桂颗粒的抗抑郁功效与腺苷和腺苷A1受体的调节有关。代谢组学分析表明，柴桂颗粒和腺苷对嘌呤代谢有显著的调节作用，对外周血单个核细胞（PBMC）的调节作用明显优于血浆。此外，靶向定量分析表明，给予柴桂颗粒和腺苷后，所有八种嘌呤代谢产物均发生了逆转。同时给予腺苷A1受体拮抗剂可能会减轻柴桂颗粒对嘌呤代谢产物的调节作用。最后，分子生物学结果表明，柴桂颗粒的抗抑郁作用可能由A1R受体介导，并且它可以通过调节CAMP-PKA-CREB-BDNF通路发挥抗抑郁作用。
