Kai-Xin-San Has Antidepressant-Like Effect in Tricyclic Antidepressant Treatment Resistant Animal Model by Rebalancing Tryptophan Metabolism.

Objective: To investigate the effect of Kai-Xin-San (KXS), alone and in combination with imipramine (IMI), to ameliorate treatment-resistant depression (TRD) by normalizing tryptophan (TRP) metabolism.

Methods: Sixty Wistar rats were randomly divided into 6 groups using the lottery method (10 rats per group): control, adrenocorticotropic hormone (ACTH), IMI, KXS, KXS+IMI, and IMI+lithium (LIT). The control group received a vehicle solution, while the others were treated with ACTH (100 µg/d) for 14 days, and concurrently, KXS (365.4 mg/kg), IMI (10 mg/kg) and LIT (100 mg/kg) were administered to ACTH-treated rats for 15 days. The behavioral tests including forced swimming test (FST) and open-field test (OFT) were performed. The state of the hypothalamic-pituitary-adrenal (HPA) axis, the levels of key enzymes and critical products in TRP metabolism, the neuroinflammatory response and the expression of serotonin (5-HT) receptors, and the alterations in the glutamatergic signaling pathway were assessed. Furthermore, molecular docking was conducted to screen the major bioactive compounds in KXS.

Results: Compared with the ACTH group, KXS and KXS+IMI effectively deceased the immobility time in FST (P<0.01), increased the total distance, number of standing, center time, and center entries in OFT (P<0.05 or P<0.01), and attenuated the serum levels of ACTH and corticosterone (P<0.05 or P<0.01). KXS and KXS+IMI mitigated the disturbances in TRP catabolism by increasing kynurenine amino transferases, tryptophan hydroxylase, 5-HT and kynurenic acid levels while attenuating tryptophan-2,3-dioxygenase (TDO), kynurenine-3-monooxygenase, kynurenine/TRP ratio, and quinolinic acid in hippocampus or liver (P<0.05 or P<0.01). Additionally, KXS and KXS+IMI not only reduced the levels of neuroinflammation and serotonin 2A receptor, also rectified abnormalities in the glutamatergic system by activating brain-derived neurotrophic factor-mammalian target of rapamycin pathway in hippocampus of ACTH-challenged rats (P<0.05 or P<0.01). Moreover, molecular docking indicated that pachymic acid, ginsenoside Rg1 and tenuifolin could bind to TDO.

Conclusions: The therapeutic potential of KXS, especially combined with IMI, for TRD owed to its safeguarding effects on TRP metabolism. Pachymic acid, ginsenoside Rg1 and tenuifolin may be the primary contributors to these protective impacts of KXS.