Omija (Schisandra chinensis) extract and soybean mixture to enhance memory function through the gut-brain axis: network pharmacology and in vivo validation of multi-target mechanisms

Abstract With the growing prevalence of memory impairment and limited treatment options, this study evaluated the cognitive-enhancing potential of an Omija ( Schisandra chinensis (Turcz). Baill) 50% ethanol extract and soybean mixture (OSM). By integrating network pharmacology with in vivo validation, we aimed to elucidate the molecular mechanisms and therapeutic efficacy of OSM. Network pharmacology was used to identify core pathways and targets associated with the memory-enhancing effects of Omija (gomisin, schizandrin) and soybean. To validate these findings, scopolamine-induced memory-impaired rats (2 mg/kg/day for 8 weeks) through the parasympathetic nervous system (PNS) suppression were administered OSM (100, 250, or 750 mg/kg/day) or dextrin (positive control) alongside a high-fat diet. Behavioral, metabolic, and molecular evaluations were conducted. Network analysis identified key targets involved in neuroinflammation including interleukin (IL)-17 and nuclear factor Kappa B (NF-κB) signaling and neurotransmitter regulation (dopamine synapse), including acetylcholinesterase (AChE), prostaglandin-endoperoxide synthase-2 (PTGS2), glycogen-synthase kinase-3beta (GSK-3β), solute carrier family 6 member 3 (SLC6A3; dopamine transporter), and plasminogen activator (PLAU). In vivo, OSM at 250 and 750 mg/kg significantly improved memory performance across passive avoidance, Y-maze, Morris water maze, and novel object recognition tests. These improvements were associated with suppressed neuroinflammatory genes ( NF-κB, PTGS2, TNF-α, IL-17, IL-1β ), enhanced cholinergic and dopaminergic balance (reduced AChE activity, increased dopamine), improved glucose metabolism, and upregulated neurotrophic factor expression (brain-derived neurotrophic factor , ciliary neurotrophic factor). Furthermore, OSM enhanced hippocampal insulin signaling (increased phosphorylation of Akt and GSK-3β), improved intestinal morphology, and increased portal vein butyrate levels, suggesting modulation of the gut-brain axis. In conclusion , OSM enhances memory through multiple central (cholinergic, dopaminergic, neurotrophic) and peripheral (anti-inflammatory, metabolic) mechanisms via activating the gut-brain axis. These findings support OSM (250–750 mg/kg) as a promising candidate for cognitive enhancement potentially by inhibiting PNS suppression, warranting further clinical investigation. Graphical abstract