Yao Lei, Chen Chao, Jing Rui, Wang Chao-Chen, Wang Yuan-Bo, Li Xia, Mu Li-Hua, Yin Hong, Liu Ping, Hu Yuan
Department of Pharmacy, Medical Supplier Center, Chinese PLA General Hospital, Beijing, 100853, China.
Graduate School of PLA General Hospital, Beijing, 100853, China.
Chin J Integr Med. 2025 Sep 12. doi: 10.1007/s11655-025-3935-5.
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.
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.
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.
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.
研究开心散（KXS）单独及与丙咪嗪（IMI）联合使用，通过使色氨酸（TRP）代谢正常化来改善难治性抑郁症（TRD）的效果。
采用抽签法将60只Wistar大鼠随机分为6组（每组10只）：对照组、促肾上腺皮质激素（ACTH）组、IMI组、KXS组、KXS + IMI组和IMI + 锂盐（LIT）组。对照组给予赋形剂溶液，其他组用ACTH（100 μg/d）治疗14天，同时，对接受ACTH治疗的大鼠给予KXS（365.4 mg/kg）、IMI（10 mg/kg）和LIT（100 mg/kg），持续15天。进行强迫游泳试验（FST）和旷场试验（OFT）等行为测试。评估下丘脑 - 垂体 - 肾上腺（HPA）轴状态、TRP代谢中关键酶和关键产物的水平、神经炎症反应和5-羟色胺（5-HT）受体的表达，以及谷氨酸能信号通路的改变。此外，进行分子对接以筛选KXS中的主要生物活性化合物。
与ACTH组相比，KXS组和KXS + IMI组有效减少了FST中的不动时间（P < 0.01），增加了OFT中的总距离、站立次数、中央时间和进入中央区域的次数（P < 0.05或P < 0.01），并降低了血清ACTH和皮质酮水平（P < 0.05或P < 0.01）。KXS组和KXS + IMI组通过增加犬尿氨酸转氨酶、色氨酸羟化酶、5-HT和犬尿酸水平，同时降低海马或肝脏中的色氨酸-2,3-双加氧酶（TDO）、犬尿氨酸-3-单加氧酶、犬尿氨酸/TRP比值和喹啉酸，减轻了TRP分解代谢的紊乱（P < 0.05或P < 0.01）。此外，KXS组和KXS + IMI组不仅降低了神经炎症水平和5-羟色胺2A受体水平，还通过激活ACTH刺激大鼠海马中的脑源性神经营养因子 - 雷帕霉素哺乳动物靶点通路纠正了谷氨酸能系统的异常（P < 0.05或P < 0.01）。此外，分子对接表明茯苓酸、人参皂苷Rg1和细叶远志皂苷可与TDO结合。
KXS，特别是与IMI联合使用时，对TRD具有治疗潜力，这归因于其对TRP代谢的保护作用。茯苓酸、人参皂苷Rg1和细叶远志皂苷可能是KXS这些保护作用的主要贡献者。
