LAUSR

BACKGROUND Gouty arthritis (GA) is a common form of inflammatory arthritis caused by intra-articular deposition of monosodium urate (MSU) crystals. However, it can not be cured at present. OBJECTIVE The goal of this work was to investigate a novel leflunomide analogue, N-(2,4-dihydroxyphenyl)-5-methyl -1,2-oxazole-3-carboxamide (UTLOH-4e), for its potential to prevent/treat gouty arthritis. METHODS In this study, the anti-inflammatory activity of UTLOH-4e was evaluated by the MSU-induced GA model in vivo and in vitro, and the molecular docking test was applied to estimate the affinity of UTLOH-4e/leflunomide for NLRP3, NF-κB, and MAPK respectively. RESULTS In vitro, UTLOH-4e (1~100 μM) treatment inhibited the inflammatory reaction with no obvious cytotoxicity in PMA-induced THP-1 macrophage exposed to MSU crystals for 24 h, involving the prominent decreased production and gene expression of IL-1β, TNF-α and IL-6. Western blot analyses demonstrated that UTLOH-4e (1~100 µM) significantly suppressed the activation of NLRP3 inflammasomes, NF-κB, and MAPK pathways. Furthermore, MSU crystal-induced rat gout arthritis confirmed that UTLOH-4e markedly ameliorated rat paw swelling, synovium inflammation and reduced the concentration of IL-1β and TNF-α in serum through down-regulating NLRP3 protein expression. CONCLUSION These results manifested that UTLOH-4e ameliorates GA induced by MSU crystals, which contribute to the modulation of NF-κB/ NLRP3 signaling pathway, suggesting that UTLOH-4e is a promising and potent drug candidate for the prevention and treatment of gouty arthritis.