Extraction Methods and Sedative–Hypnotic Effects of Total Flavonoids from Ziziphus jujuba Mesocarp

<b>Background/Objectives</b>: As a non-medicinal part resource of <i>Ziziphus jujuba</i>, this study focuses on the total flavonoids from <i>Ziziphus jujuba</i> mesocarp (TFZJM), aiming to optimize the extraction process and explore its sedative and hypnotic effects. <b>Methods</b>: The extraction process of TFZJM was optimized by using single-factor experiments and the Box-Behnken response surface design method. The material basis of TFZJM was analyzed using Ultra-Performance Liquid Chromatography-Quadrupole-Time of Flight-Mass Spectrometry (UPLC-Q-TOF-MS). The mouse insomnia model was induced by intraperitoneal injection of PCPA, and the effects of TFZJM on this model and its potential mechanism were evaluated using multiple methods, such as sleep enhancement induced by pentobarbital sodium, HE staining of tissue sections, ELISA, RT-PCR, WB, and serum metabolomics. <b>Results</b>: The results showed that by optimizing the extraction conditions, a solid-liquid ratio (SLR) of 1:25 g·mL^-1, ethanol concentration of 60%, extraction time of 60 min, and extraction rate of 1.98% were achieved. The common chemical basis of the 10 flavonoid components was identified using UPLC-Q-TOF-MS analysis. Compared with the model group, the high-dose TFZJM (TFZJM-H) group had the most significant effect, followed by the medium-dose (TFZJM-M) and low-dose (TFZJM-L) groups. <b>Conclusions</b>: Metabolomic analysis revealed that TFZJM regulates pathways related to the metabolism of phenylalanine, tyrosine, cytochrome P450, and alanine. This lays the foundation for further exploration of the active substances and mechanisms of action of TFZJM in sedation and hypnosis.