Metabolomics-based alleviation of depression by Xiaoyaosan through regulation of XDH and GRIA2

Abstract

BackgroundXiaoyaosan is gradually gaining acceptance and recognition within the international scientific community. However, it still lacks appropriate methodological and theoretical descriptions that adhere to modern scientific standards. The development of omics technologies, particularly metabolomics, has facilitated the characterization of body physiology and can be used to guide clinical intervention. Aim of this studyThis study explored the therapeutic mechanism of Xiaoyaosan from a metabolomics perspective. MethodsWe recruited a total of 30 patients with mild to moderate depression and 15 healthy individuals, and collected urine samples from these participants for non-targeted metabolomics analysis. To establish a depressed rat model, we used chronic unpredictable mild stress in combination with orphan, and collected urine samples from the depressed rats for untargeted metabolomics analysis. Differential metabolites (DMs) were analyzed using multivariate data methods, and the biological pathways of DMs were analyzed using MetaboAnalyst 5.0. We comprehensively analyzed the urine metabolic fingerprints of depressed patients and rats to explore common characteristics of metabolic pathways and markers. We also analyzed the key targets of Xiaoyaosan in the treatment of depression and compared them to the targets of metabolic biomarkers. Finally, we verified the regulatory effects of Xiaoyaosan on key targets using real-time quantitative PCR and Western blot. ResultsIn the treatment of depression patients with Xiaoyaosan, we identified 243 DMs and 22 metabolic pathways. For depressed rats treated with Xiaoyaosan, we found 44 DMs and 9 metabolic pathways. Our comprehensive analysis of the urinary metabolic fingerprint revealed 7 important biological pathways and 6 crucial metabolic markers in the treatment of depression with Xiaoyaosan. The key targets of Xiaoyaosan in the treatment of depression were identified as XDH and GRIA2. Real-time quantitative PCR results demonstrated that Xiaoyaosan upregulated XDH expression in the brain's prefrontal cortex and GRIA2 expression in the brain's prefrontal cortex and hippocampus of depressed rats. Western blot results indicated that Xiaoyaosan upregulated XDH expression in the hypothalamus, prefrontal cortex, and hippocampus, as well as GRIA2 expression in the prefrontal cortex and hippocampus of depressed rats. ConclusionsOur study demonstrated that Xiaoyaosan regulates the metabolic disorders of depression and plays an antidepressant role through regulation of the expression of XDH and GRIA2 in the brain tissues of CUMS rats.