Combining Metabolomics and Quantitative Analysis to Investigate Purine Metabolism Disorders in Depression and the Therapeutic Effect of Chaigui Granules

Abstract

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.

Keywords: Chaigui granules; adenosine; antidepressant mechanism; cAMP-PKA-CREB-BDNF pathway; purine metabolism.