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

Abstract

Purpose

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

Statement

The present study was partly based on the clinical trial “A randomized, double-blind, placebo-controlled clinical trial on the efficacy and safety of Shen-Zhi-Ling tablets in the treatment of depression. (heart and spleen deficiency syndrome)”. The Chinese PLA General Hospital was the sponsor of the trial. The patients who provided the serum samples in the paper were enrolled and treated in Xijing Hospital of The Fourth Military Medical University of the Chinese People’s Liberation Army. The protocol was approved by the Ethics Committee of Xijing Hospital.

Ethics Approval and Informed Consent

Experimental protocols relating human subjects have been reviewed and approved by the Ethics Committee of Xijing Hospital of The Fourth Military Medical University of the Chinese People’s Liberation Army (Xi’an China, Ethical approval No. YS201505074). All the participants have signed written inform consent. The animal experimental procedures were approved by the Animal Experimentation Ethics Committee of PLA General Hospital. The present research followed the Instructive Notions with Respect to Caring for Laboratory Animals, the Ministry of Science and Technology of China (13 September 2006).

Acknowledgments

The present study was supported by National Natural Science Foundation of China (No. 81973502).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.