Mechanistic Study of Schisandrin B in Alleviating Anxiety-Like Behaviors in Rats via Enhancement of Hippocampal Synaptic Plasticity and Restoration of the Intestinal Barrier.

This study focused on examining the anxiolytic effects of Schisandrin B (SchB) in rats exhibiting anxiety-like behaviors and investigating the mechanisms involved. Behavioral assessments were conducted using the elevated plus-maze test and the open field test. The results showed that Schisandrin B at a dose of 10 mg/kg significantly alleviated anxiety-like behaviors in rats, with an efficacy comparable to that of the positive control drug diazepam. Mechanistic studies indicate that, at the central level, Schisandrin B effectively maintains the homeostasis of the glutamatergic system in the hippocampus and the HPA axis. Specifically, Schisandrin B downregulates the stress-induced overexpression of ionotropic glutamate receptor subunits at both the mRNA and protein levels, including NMDAR subtypes (GluN1A, GluN2A, and GluN2B) and AMPAR subtypes (GluA1 and GluA2), thereby restoring the glutamate/γ-aminobutyric acid (Glu/GABA) ratio to physiological levels. In addition, Schisandrin B suppresses the hyperactivation of the HPA axis by reducing the secretion of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone (CORT). Meanwhile, it ameliorates neuronal and synaptic ultrastructural damage in the hippocampus and upregulates the expression of synaptic plasticity-related proteins, SYP and PSD-95, thereby improving synaptic transmission and function. At the peripheral intestinal level, Schisandrin B alleviated colon shortening in anxiety-model rats and reduced fecal pH, thereby improving intestinal environmental homeostasis. Schisandrin B also promoted the upregulation of tight junction proteins (ZO-1, Occludin, and Claudin-1) in the colonic tissues, contributing to the restoration of colonic mucosal integrity, attenuation of inflammatory infiltration, and reinforcement of intestinal barrier function. Collectively, Schisandrin B exerts systemic anxiolytic effects by centrally regulating hippocampal glutamatergic neurotransmission, HPA axis activity, and synaptic plasticity, while simultaneously repairing peripheral intestinal barrier dysfunction. These results indicate the potential of Schisandrin B as a therapeutic candidate for anxiety disorders.