Kai-Xin-San improves CUMS-induced depression by regulating the tryptophan - 5-hydroxytryptophan -5-HT pathway

Kai-Xin-San (KXS) is a traditional Chinese medicinal formulation utilized for millennia to address depression. It was initially documented in Bei Ji Qian Jin Yao Fang, authored by Sun Simiao during the Tang Dynasty. Nonetheless, there exists a paucity of studies about the potential mechanisms and comprehensive effects of KXS on depression.

The objective of the study was to elucidate the probable mechanisms by which KXS ameliorates depression at various levels through metabolomics and transcriptomics, assess the therapeutic benefits of KXS on depression via in vivo and in vitro studies, and investigate its putative mechanisms of action.

This study used single-cage management combined with chronic unpredictable mild stress rats as the model, and UHPLC-Q-TOF MS/MS technology was used to draw metabolic maps through serum and urine overall metabolomics methods. Subsequently, transcriptome studies were used to explore the key differential genes and pathways of KXS in improving depression, and the association with metabolomics was established. UPLC-TQ-MS method was used to determine tryptophan metabolites, and the changes of tryptophan metabolites in vivo were comprehensively investigated. And at the same time used enterochromaffin cells (EC cells) as the in vitro research model to explore the potential mechanism of KXS in the treatment of depression.

Pharmacological results showed that KXS significantly improved hyperfunction of the hypothalamic-pituitary-adrenal axis, improved damage of intestinal barrier and increased the expression of brain-derived neurotrophic factor in hippocampus. The global metabolomics of serum and urine showed that KXS could significantly reverse the metabolic spectrum disorder of depressed rats. The results of the association analysis with transcriptomics showed that KXS could improve depression by regulating the tryptophan pathway. Subsequently, the contents of several tryptophan (Trp) metabolites in the colon, serum and brain were detected by UPLC-TQ MS/MS. Combined with the results of cell experiments, it is shown that KXS can increase the secretion of 5-hydroxytryptophan (5-HTP) by EC cells. Intestinal-derived 5-HTP is absorbed into circulation and penetrates the blood-brain barrier, elevating central 5-HT levels to alleviate depressive symptoms.

KXS may exert antidepressant effects by regulating the Trp -5-HTP-5-HT metabolic pathway in the body. This research will offer novel understanding of the mechanism by which KXS operates in the treatment of depression.