Paeoniflorin alleviates anxiety-like behaviors in sleep-deprived male mice by suppressing inflammation of the paraventricular nucleus of the hypothalamus.

Abstract

<p>BACKGROUND: Insomnia represents a major global health challenge, with profound detrimental effects on physical and mental well-being. Paeoniflorin (PF), a bioactive component derived from Paeonia lactiflora Pall. (known as "Shao Yao" in traditional Chinese medicine, TCM), has garnered growing interest for its potential in the management of mental disorders. PURPOSE: The present study was designed to: 1) evaluate the effects of PF on anxiety-like behaviors, body weight changes, and the levels of inflammatory factors in sleep-deprived (SD) mice; 2) determine its optimal therapeutic dose; and 3) explore the underlying mechanisms of action. METHODS: Male C57BL/6 mice (n=8 per group) were randomly divided into six experimental groups: Control, SD + Saline, SD + 15 mg/kg PF, SD + 30 mg/kg PF, SD + 60 mg/kg PF, and SD + 0.5 mg/kg Diazepam (DZP). Mice in the PF-treated groups received daily intraperitoneal injections of PF for the entire duration of the SD protocol. To identify the brain regions targeted by PF, c-Fos immunofluorescence staining and chemogenetic approaches were employed. Additionally, network pharmacology, molecular docking, and molecular dynamics simulations were utilized to predict and validate the potential molecular targets of PF. Finally, the western blot experiment was used for verification. RESULTS: This study demonstrated that PF effectively attenuated anxiety-like behaviors in SD mice. Mechanistically, this beneficial effect was associated with the inhibition of three key pathological processes in SD mice: excessive activation of the paraventricular nucleus of the hypothalamus (PVN), aberrant phosphorylation of the epidermal growth factor receptor/phosphatidylinositol 3-kinase/protein kinase B (EGFR/PI3K/AKT) signaling pathway, and abnormally elevated inflammatory responses. CONCLUSION: PF alleviates SD-induced anxiety by curbing PVN hyperactivity, EGFR/PI3K/AKT hyper-phosphorylation and neuroinflammation, offering a multi-target therapeutic strategy for SD-related disorders.</p>