基于血清代谢组学和网络药理学研究酸枣仁提取物治疗失眠的效应物质及作用机制

基于血清代谢组学和网络药理学研究酸枣仁提取物治疗失眠的效应物质及作用机制.建立对氯苯丙氨酸(p-chlorophenylalanine,PCPA)诱导大鼠失眠模型,酸枣仁提取物灌胃给药后,进行一般形态观察、戊巴比妥钠诱导失眠实验和病理组织学等药效学评价.采用UHPLC-MS代谢组学技术,结合多元数据统计筛选酸枣仁提取物...

Effective substance and mechanism of Ziziphi Spinosae Semen extract in treatment of insomnia based on serum metabolomics and network pharmacology

This study aims to study the effective substance and mechanism of Ziziphi Spinosae Semen extract in the treatment of insomnia based on serum metabolomics and network pharmacology.The rat insomnia model induced by p-chlorophenylalanine(PCPA)was established.After oral administration of Ziziphi Spinosae Semen extract,the general morphological observation,pentobarbital sodium-induced sleep test,and histopathological evaluation were carried out.The potential biomarkers of the extract in the treatment of insomnia were screened by ultra-high performance liquid chromatography-mass spectrometry(UHPLC-MS)combined with multivariate analysis,and the related metabolic pathways were further analyzed.The"component-target-pathway"network was constructed by ultra-high performance liquid chromatography coupled with quadrupole-Exactive mass spectrometry(UHPLC-Q-Exactive-MS/MS)combined with network pharmacology to explore the effective substances and mechanism of Ziziphi Spinosae Semen in the treatment of insomnia.The results of pentobarbital sodium-induced sleep test and histopathological evaluation(hematoxylin and eosin staining)showed that Ziziphi Spinosae Semen extract had good theraputic effect on insomnia.A total of 21 endogenous biomarkers of Ziziphi Spinosae Semen extract in the treatment of insomnia were screened out by serum metabolomics,and the metabolic pathways of phenylalanine,tyrosine and tryptophan biosynthesis,phenylalanine metabolism,and nicotinate and nicotinamide metabolism were obtained.A total of 34 chemical constituents were identified by UHPLC-Q-Exactive-MS/MS,including 24 flavonoids,2 triterpenoid saponins,4 alkaloids,2 triterpenoid acids,and 2 fatty acids.The network pharmacological analysis showed that Ziziphi Spinosae Semen mainly acted on target proteins such as dopamine D2 receptor(DRD2),5-hydroxytryptamine receptor 1 A(HTR1 A),and alpha-2 A adrenergic receptor(ADRA2 A)in the treatment of insomnia.It was closely related to neuroactive ligand-receptor interaction,serotonergic synapse,and calcium signaling pathway.Magnoflorine,N-nornuciferine,caaverine,oleic acid,palmitic acid,coclaurine,betulinic acid,and ceanothic acid in Ziziphi Spinosae Semen may be potential effective compounds in the treatment of insomnia.This study revealed that Ziziphi Spinosae Semen extract treated insomnia through multiple metabolic pathways and the overall correction of metabolic disorder profile in a multi-component,multi-target,and multi-channel manner.Briefly,this study lays a foundation for further research on the mechanism of Ziziphi Spinosae Semen in treating insomnia and provides support for the development of innovative Chinese drugs for the treatment of insomnia.