目的 基于 ¹H-NMR動態(tài)代謝組學和整合網(wǎng)絡藥理學探究柴歸顆粒調(diào)控慢性溫和不可預知應激（CUMS）大鼠尿液代謝標志物發(fā)揮抗抑郁作用的關鍵途徑和潛在靶點。方法 除對照組外，各組大鼠均進行 7周 CUMS造模，前 4周僅造模，后 3周 ig給藥 1 h后造模并對鹽酸文拉法辛（35 mg·kg^-1）組和柴歸顆粒（8.3 g·kg^-1）組進行藥物干預，通過稱體質(zhì)量、糖水偏愛實驗、強迫游泳實驗研究柴歸顆粒的抗抑郁作用；收集各組大鼠不同時間節(jié)點的尿液，采用 ¹H-NMR代謝組學監(jiān)測柴歸顆粒給藥過程中尿液代謝標志物的動態(tài)變化規(guī)律，整合網(wǎng)絡藥理學分析挖掘其治療抑郁癥的關鍵途徑和潛在靶點。結(jié)果 與模型組比較，柴歸顆粒顯著增加大鼠的體質(zhì)量（P＜0.05），顯著升高糖水偏愛率（P＜0.01），顯著減少游泳不動時間（P＜0.05、0.01）；柴歸顆?？梢詣討B(tài)調(diào)控天冬氨酸等10個尿液代謝標志物接近正常水平，且不同代謝物回調(diào)至正常水平的給藥周期不同，泛酸、馬尿酸含量在柴歸顆粒給藥1周后顯著回調(diào)（P＜0.05、0.01）；蛋氨酸、甲胺和天冬氨酸含量在柴歸顆粒給藥2周后顯著回調(diào)（P＜0.01）；2-酮戊二酸、牛磺酸、丁酸、賴氨酸和乳酸含量在柴歸顆粒給藥3周后顯著回調(diào)（P＜0.05、0.01）。同時，網(wǎng)絡藥理學分析結(jié)果表明柴歸顆粒可能通過調(diào)控丙氨酸、天冬氨酸和谷氨酸代謝這一關鍵途徑發(fā)揮療效，且其代謝途徑上的GPT、GLUD1、GLUD2、GOT2等4個靶點可能是柴歸顆粒治療抑郁癥的潛在靶點。結(jié)論 柴歸顆?？赡芡ㄟ^調(diào)控丙氨酸、天冬氨酸和谷氨酸代謝這一關鍵途徑發(fā)揮抗抑郁作用。

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

國家自然科學基金資助項目（82374153）；山西省基礎研究計劃項目（202103021224026）