目的 基于 ¹H-NMR动态代谢组学和整合网络药理学探究柴归颗粒调控慢性温和不可预知应激（CUMS）大鼠尿液代谢标志物发挥抗抑郁作用的关键途径和潜在靶点。方法 除对照组外，各组大鼠均进行 7周 CUMS造模，前 4周仅造模，后 3周 ig给药 1 h后造模并对盐酸文拉法辛（35 mg·kg^-1）组和柴归颗粒（8.3 g·kg^-1）组进行药物干预，通过称体质量、糖水偏爱实验、强迫游泳实验研究柴归颗粒的抗抑郁作用；收集各组大鼠不同时间节点的尿液，采用 ¹H-NMR代谢组学监测柴归颗粒给药过程中尿液代谢标志物的动态变化规律，整合网络药理学分析挖掘其治疗抑郁症的关键途径和潜在靶点。结果 与模型组比较，柴归颗粒显著增加大鼠的体质量（P＜0.05），显著升高糖水偏爱率（P＜0.01），显著减少游泳不动时间（P＜0.05、0.01）；柴归颗粒可以动态调控天冬氨酸等10个尿液代谢标志物接近正常水平，且不同代谢物回调至正常水平的给药周期不同，泛酸、马尿酸含量在柴归颗粒给药1周后显著回调（P＜0.05、0.01）；蛋氨酸、甲胺和天冬氨酸含量在柴归颗粒给药2周后显著回调（P＜0.01）；2-酮戊二酸、牛磺酸、丁酸、赖氨酸和乳酸含量在柴归颗粒给药3周后显著回调（P＜0.05、0.01）。同时，网络药理学分析结果表明柴归颗粒可能通过调控丙氨酸、天冬氨酸和谷氨酸代谢这一关键途径发挥疗效，且其代谢途径上的GPT、GLUD1、GLUD2、GOT2等4个靶点可能是柴归颗粒治疗抑郁症的潜在靶点。结论 柴归颗粒可能通过调控丙氨酸、天冬氨酸和谷氨酸代谢这一关键途径发挥抗抑郁作用。

Objective ¹H-NMR dynamic metabonomics and integrated network pharmacology were used to explore the key pathways and potential targets of Chaigui Granules (CGG) in regulating the antidepressant effect of chronic unpredictable mild stress (CUMS) rats urinary metabolic markers. Methods Except the control group, CUMS model was made in all groups for 7 weeks, and only in the first 4 weeks, 1 hour after ig administration for 3 weeks, the model was established and the drug intervention was carried out in venlafaxine (35 mg·kg^-1) and CGG (8.3 g·kg^-1), study the antidepressant effect of CGG through body weight, sugar water preference experiment, and forced swimming experiment. The urine was collected at different time points. ¹H-NMR metabonomics was used to monitor the dynamic changes of urinary metabolic markers during the administration of CGG, and to explore the key pathways and potential targets of CGG in the treatment of depression by integrated biological network analysis. Results Compared with the model group, CGG significantly increased the body weight of rats (P <0.05), significantly increased the sugar water preference rate (P <0.01), and significantly reduced the swimming immobility time (P <0.05, 0.01). The results showed that CGG could dynamically modulate 10 urinary metabolic markers such as Aspartate to near normal levels, and the administration cycle of different metabolites to normal levels was different. The levels of pantothenate and hippurate were significantly reduced one week after CGG administration (P <0.05, 0.01). Methionine, methylamine and aspartate were significantly reduced two weeks after CGG administration (P <0.01), 2-oxoglutarate, taurine, butyrate, lysine and lactic acid were significantly reduced after three weeks of CGG administration (P <0.05、0.01). At the same time, the results of network pharmacology analysis indicated that CGG might exert its therapeutic effect by adjusting the key pathway of alanine, aspartate and glutamate metabolism, the four targets of GPT, GLUD1, GLUD2 and GOT2 in the metabolic pathway may be potential targets of CGG in the treatment of depression. Conclusion This study explored the mechanism of CGG in the treatment of depression from ¹H-NMR dynamic metabolomics and biological network analysis, and provided a scientific theoretical basis for the clinical application of CGG.

R285.5

国家自然科学基金资助项目（82374153）；山西省基础研究计划项目（202103021224026）