Objective:

2

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:

2

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:

2

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:

2

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.