Bridging Bench and Bytes: Syringic Acid and Nifuroxazide Reduce Stress-Induced Anxiety via NF-κB/NLRP3 Modulation and Docking Validation.

Anxiety disorders are among the most prevalent neuropsychiatric conditions, with oxidative stress, neuroinflammation, and serotonergic dysfunction contributing to their pathogenesis. Novel therapeutic approaches targeting these mechanisms are urgently required. The present study evaluated the anxiolytic potential of syringic acid (SA), nifuroxazide (NFU), and their combinations in a restraint stress-induced mouse model of anxiety. Behavioral parameters were assessed using the elevated plus maze, light-dark box, open field, and marble burying tests. Biochemical markers of oxidative stress, including superoxide dismutase (SOD) and glutathione (GSH), were quantified, along with pro-inflammatory mediators NLRP3, NF-κB, TNF-α, and IL-1β. Serotonin levels were measured by ELISA. Molecular docking studies were performed to explore the binding interactions of SA with NLRP3 and NFU with NF-κB. Restraint stress induced significant anxiety-like behavior, oxidative imbalance, and upregulation of inflammatory markers, accompanied by reduced serotonin levels. SA treatment significantly improved behavioral performance, restored SOD and GSH activity, and reduced NLRP3, NF-κB, TNF-α, and IL-1β levels. NFU alone showed minimal behavioral and biochemical benefits but, in combination with SA (particularly at full dose), produced marked anxiolytic effects, attenuated inflammation, and partially restored serotonin concentrations. Docking studies supported these findings, revealing stable interactions of SA with NLRP3 and NFU with NF-κB. Syringic acid demonstrates potent anxiolytic activity, mediated through antioxidant, anti-inflammatory, and serotonergic modulation. Its combination with nifuroxazide further enhances these effects, highlighting a promising therapeutic strategy against anxiety disorders.