Usnic acid attenuates inflammation and joint damage in Freund's complete adjuvant-induced arthritis in rats

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and functional disability. Usnic acid (UA), a lichen‑derived secondary metabolite, has shown anti‑inflammatory and antioxidant potential in preclinical models. This study evaluated the effects of UA in Freund's complete adjuvant (FCA)‑induced arthritis in rats and its impact on key inflammatory and oxidative biomarkers. Arthritis was induced by a single subplantar injection of FCA (0.15 mL), followed by oral administration of UA (25, 50, 100 mg/kg) and the reference drug piroxicam (10 mg/kg) for 15 days, with an additional group receiving HDUA (100 mg/kg) plus piroxicam. Disease severity and treatment response were assessed by measuring body weight, paw thickness, arthritic and joint stiffness scores, hematological indices, liver and kidney function markers, oxidative stress parameters (SOD, CAT, MDA), pro‑inflammatory cytokine and signaling mRNA expression (TNF‑α, IL‑1β, IL‑6, NF‑κB, COX‑2), and ankle joint histopathology and radiology. UA attenuated (p < 0.0001) FCA‑induced weight loss and reduced paw edema, arthritic scores, and joint stiffness versus arthritic controls, while improving RBC count and Hb and decreasing platelet count, TLC, urea, and creatinine (p < 0.001). UA also increased SOD and CAT activities, reduced MDA (p < 0.001), downregulated TNF‑α, IL‑1β, IL‑6, NF‑κB, and COX‑2 mRNA, and improved joint histology and radiographic appearance. UA thus exhibits anti‑inflammatory and antioxidant properties and represents a promising lead for further preclinical evaluation in RA, although additional studies are needed to better define its safety profile.