KXS Balances the Tryptophan Metabolism in Mild to Moderate Depressed Patients and Chronic Restraint Stress Induced Depressive Rats

Yuanbo Wang1,2 *, Xia Li1,2 *, Rui Jing,2 Wenshan Yang,1,2 Yichen Wang,1,2 Chaochen Wang,1,2 Lei Yao,1,2 Xiaoming Cui,3 Yuan Hu2 1Graduate School of PLA General Hospital, Beijing, 100853, People’s Republic of China; 2Department of Pharmacy, Medical Supplies Center of PLA General Hospital, Beijing, 100853, People’s Republic of China; 3Department of Health Medicine, The Third Medical Center of PLA General Hospital, Beijing, 100039, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoming Cui, Department of Health Medicine, The Third Medical Center of PLA General Hospital, Beijing, 100039, People’s Republic of China, Email 18611206336@163.com Yuan Hu, Department of Pharmacy, Medical Supplies Center of PLA General Hospital, No. 28 FuXing Road, Beijing, 100853, People’s Republic of China, Email huyuan1980619@126.comPurpose: Tryptophan metabolism is involved in the etiology and exacerbation of depressive disorders. Kai-Xin-San (KXS), a traditional Chinese medicine formula, has been widely used to treat depression and modulate serotonin simultaneously, but how it regulates depressive-like behavior by shifting the balance of the tryptophan-serotonin metabolism and kynurenine pathway remains vague.Patients and Methods: Ten participants with mild to moderate depression treated with KXS (KXS preparation) were analyzed in this study. Depression rating scale score and the concentration of serum tryptophan, 5-hydroxytryptophan and kynurenine was measured at baseline and the endpoint of KXS treatment. To explore the specific regulatory mechanism of KXS in tryptophan metabolism, the chronic restraint stress (CRS) was used to induce depressive-like syndrome in rats and the hippocampus level of tryptophan, 5-hydroxytryptophan, kynurenine with downstream metabolites (kynurenic acid, quinolinic acid) and key enzymes (indoleamine 2,3-dioxygenase, kynurenine 3-monooxygenase, kynurenine aminotransferase) were analyzed by liquid chromatography–electros pray ionization tandem mass spectrometry, high performance liquid chromatography and enzyme-linked immunosorbent assay respectively.Results: KXS significantly decreased depression rating scale scores and increased the serum tryptophan and kynurenine concentration in depressive patients compared to baseline. Also, it alleviated the depressive behavior in CRS rats obviously. Comparing with CRS group, KXS increased tryptophan, 5-hydroxytryptophan, kynurenine level in rat hippocampus. Furthermore, in kynurenine pathway, KXS decreased the expression of indoleamine 2,3-dioxygenase, increased kynurenic acid by upregulating the expression of kynurenine aminotransferase while decreased quinolinic acid level in hippocampus, which suggested that KXS more favored improving serotonin pathway, and neuroprotective kynurenic acid branch in the tryptophan metabolism.Conclusion: This is the first tryptophan metabolomic study of patients with depression undergoing KXS treatment. Combining these clinical results with CRS induced rat model studies, it verified that KXS achieves an excellent antidepressant effect and balances tryptophan-kynurenine metabolic pathways by regulating some key metabolic products and enzymes.Keywords: depression, amino acids, TCM, KaiXinSan