目的 基于代谢组学技术考察酸枣仁总皂苷（total saponins of Ziziphi Spinosae Semen，SZSS）对失眠大鼠内源性代谢物的影响，并探讨酸枣仁总皂苷改善学习记忆的药效及其作用机制。方法 采用对氯苯丙氨酸（DL-4-chlorophenylalanine，PCPA）诱导大鼠失眠模型，给予地西泮和酸枣仁总皂苷干预后，进行旷场实验及Morris水迷宫实验；采用苏木素-伊红（HE）染色观察海马组织病理变化；采用ELISA测定海马组织5-羟色氨（5-hydroxytryptamine，5-HT）、γ-氨基丁酸（γ-aminobutyric acid，GABA）及NO （nitric oxide，NO）水平。利用UPLC-Orbitrap-MS/MS技术对大鼠海马组织代谢轮廓进行分析，结合多元统计分析筛选差异性代谢物，并基于MetaboAnalyst 5.0数据库进行代谢通路及代谢网络分析，多角度探讨酸枣仁总皂苷改善学习记忆的代谢特征及作用途径。结果 与模型组比较，酸枣仁总皂苷组大鼠学习能力显著提高（P<0.05、0.01），海马组织病理结构明显改善，海马组织中5-HT、GABA及NO水平显著升高（P<0.05、0.01）；代谢组学共鉴定出18种与学习记忆损伤相关的潜在生物标志物，酸枣仁总皂苷主要通过苯丙氨酸、酪氨酸和色氨酸等7条主要氨基酸代谢通路发挥改善记忆损伤的作用。结论 酸枣仁总皂苷能够通过回调海马组织内源性差异代谢物，并调控相关氨基酸代谢通路，从而改善失眠引起学习记忆减退。

Objective To study the effect of total saponins of Suanzaoren (Ziziphi Spinosae Semen, SZSS) on endogenous metabolites in insomnia model rats based on metabolomics, and explore the effect and mechanism of SZSS on learning and memory. Methods DL-4-chlorophenylalanine (PCPA) was used to induce insomnia model in rats, diazepam and SZSS were given for intervention. Open field experiment and Morris water maze experiment were carried out; Hematoxylin-eosin (HE) staining was used to observe the pathological changes of hippocampus; Levels of 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) and NO (nitric oxide) in hippocampus were measured by ELISA. UPLC-Orbitrap-MS/MS was used to analyze the metabolic profile of hippocampus, combined with multivariate statistical analysis to screen out the different metabolites, and based on MetaboAnalyst 5.0 database, metabolic pathway and metabolic network were analyzed, metabolic characteristics and action ways of SZSS to improve learning and memory were discussed from various angles. Results Compared with model group, learning ability of rats in SZSS group was significantly improved (P < 0.05, 0.01), pathological structure of hippocampus was significantly improved, levels of 5-HT, GABA and NO in hippocampus were significantly increased (P < 0.05, 0.01). A total of 18 potential biomarkers related to learning and memory impairment had been identified by metabonomics. SZSS mainly played a role in improving memory impairment through seven major amino acid metabolic pathways such as phenylalanine, tyrosine and tryptophan. Conclusion SZSS can improve the learning and memory loss caused by insomnia by regulating endogenous differential metabolites in hippocampus and regulating related amino acid metabolic pathways.

R285.5

山西省科技厅中央引导地方科技发展资金项目（YDZJSX2021C025）；山西省自然科学基金面上项目（20210302123237，20210302123470）；山西省卫生健康委“十大晋药”项目（ZYCZL2020007）；山西中医药大学青年科学家培育项目（2021PY-QN-07）