目的 分析脑灵片治疗失眠症的效应生物标记物及关联体内显效成分，揭示脑灵片治疗失眠症的药效物质基础。方法 建立对氯苯丙氨酸诱导的失眠症大鼠模型，利用UPLC-Q/TOF-MS技术鉴定血清生物标记物及脑灵片治疗的效应生物标记物，同时利用UPLC-Q/TOF-MS技术表征脑灵片血中移行成分，通过Spearman关联度分析构建脑灵片血中移行成分与效应生物标记物的关联热图，提取高度关联的血中移行成分作为脑灵片治疗失眠症的药效物质基础。结果 脑灵片能够显著回调肾上腺酸、花生四烯酸、鹅去氧胆酸、L-乙酰肉碱、L-苯丙氨酸、L-色氨酸、L-酪氨酸、油酰胺、泛酸、视黄酯10个失眠症大鼠模型生物标记物，与生物标记物高度相关的脑灵片血中移行成分为绿原酸、4-羟基肉桂酸、木兰花碱、远志(口山)III、3,6'-二芥子酰基蔗糖、淫羊藿苷、远志皂苷V、宝藿苷I、五味子醇甲、五味子酸、3-表去氢土莫酸、茯苓酸、脱糖羟基化宝藿苷I、二羟基化箭藿苷B硫酸酯、去甲基二氢化远志(口山)酮III。结论 利用方证代谢组学方法鉴定了脑灵片治疗失眠症的效应生物标记物，并发现了五味子醇甲、五味子酸、淫羊藿苷等为脑灵片治疗失眠症的药效物质基础，为质量标志物筛选及质量标准提升提供了科学依据。

Objective To analyze the biomarkers and associated in vivo components of Naoling Tablets (脑灵片) in treatment of insomnia, and reveal the pharmacodynamic material basis of Naoling Tablets in treatment of insomnia. Methods A rat model of insomnia induced by chlorophenylalanine was established. UPLC-Q/TOF-MS technology was used to identify serum biomarkers and effect biomarkers of Naoling Tablets. UPLC-Q/TOF-MS technology was also used to characterize the components of Naoling Tablets in the blood. Spearman correlation analysis was used to construct a heatmap of the correlation between the components of Naoling Tablets in the blood and the effect biomarkers, and the highly correlated components were extracted as the pharmacodynamic material basis for Naoling Tablets in treating insomnia.Results Naoling Tablets could significantly regulate 10 biomarkers of insomnia rat model, including adrenal acid, arachidonic acid, chenodeoxycholic acid, L-acetylcarnitine, L-phenylalanine, L-tryptophan, L-tyrosine, oleamide, pantothenic acid and retinol ester. The components of Naoling Tablets in the blood that were highly correlated with the biomarkers included chlorogenic acid, 4-hydroxycinnamic acid, magnoflorine, polygalaxanthone III, 3,6'-disinapoyl sucrose, icariin, onjisaponin V, baohuoside I, schisandrin, schisandronic acid, 3-epidehydrotumulosic acid, pachymic acid, deglycosylated hydroxylated baohuoside I, dihydroxylated sagittatosdie B sulfate and dimethyl dihydrogen polygalaxanthone III. Conclusion This study used chinmedomics method to identify the effect biomarkers of Naoling Tablets in treatment of insomnia, and found that schisandrin, schisandric acid, icariin and other substances were the pharmacodynamic material basis of Naoling Tablets in treatment of insomnia, providing a scientific basis for the screening of quality markers and the improvement of quality standards.

黑龙江省重点研发计划（2022ZX02C04）;国家自然科学基金重点项目（81830110）