LAUSR

&NA; Levetiracetam (LEV), a novel anti‐epileptic drug that has been demonstrated with an anti‐inflammatory effect, but the exact mechanisms of its action remain to be fully defined. The present study aimed to evaluate the possible effects of LEV on lipopolysaccharides (LPS)‐induced Janus kinase‐signal transducers and activators of transcription (JAK/STAT) as well as toll‐like receptor 4 (TLR4)/ mitogen activated protein kinase (MAPK) signaling pathways activation in adjuvant induced arthritis (AIA). Rats were allocated into normal control, three arthritic control groups: Complete Freund's Adjuvant (CFA) (0.4 ml/3days/12days), LPS (100 &mgr;g/kg/day), CFA+LPS, and three treated groups: CFA+LEV, LPS+LEV and CFA+LPS+LEV. LEV was administered in a dose 50 mg/kg/day for 15 day. After 28 days, tissue samples were collected for assessment of phosphorylated JAK2, STAT3, TLR4, MAPK and cathepsin K quantitative expression in synovium. Additionally, Serum samples were used for biochemical evaluation of interleukin‐6 (IL‐6), interleukin‐1beta (IL‐1B), LPS, anti‐citrullinated protein antibody (ACPA) and 8‐hydroxydeoxyguanosine (8‐OHdG). Histopathological and macroscopical examinations of joints were also performed to support our study. Results indicated that LEV exerted its anti‐inflammatory effect through inhibiting LPS‐dependent phosphorylation of JAK2/STAT3 signaling. It significantly suppressed TLR4 and MAPK expressions, thereby decreasing release of inflammatory cytokines IL‐1&bgr;, IL‐6.LEV exhibited a potent inhibitory effect on cathepsin K and 8‐OHdG parallel to confirmatory histopathological and macroscopical findings. In conclusion, LEV has a powerful therapeutic effect on adjuvant induced arthritis in rats and its mechanisms are strongly related to inhibiting excessive activation of JAK2‐STAT3 and TLR4 pathways. This may add a new approach for treatment of RA.