Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis

Objective. To evaluate the effects of SE 242235, a potent and selective inh ibitor of p38 mitogen-activated protein (MAP) kinase, on joint integrity in rats with adjuvant-induced arthritis (AIA), Methods, Male Lewis rats with AIA were orally treated either prophylactical ly (days 0-20) or therapeutically (days 10-20) with SE 242235, Efficacy was determined by measurements of paw inflammation, dual-energy x-ray absorpti ometry for bone mineral density (BMD), magnetic resonance imaging (MRI), mi cro-computed tomography (CT), and histologic evaluation. Serum tumor necros is factor alpha (TNF alpha) in normal (non-AIA) rats and serum interleukin- 6 (IL-6) levels in rats with AIA were measured as markers of the antiinflam matory effects of the compound. Results. SE 242235 inhibited lipopolysaccharide-stimulated serum levels of TNF alpha in normal rats, with a median effective dose of 3.99 mg/kg. When SE 242235 was administered to AZA rats prophylactically on days 0-20, it in hibited paw edema at 30 mg/kg and 10 mg/kg per day by 56% and 33%, respecti vely. Therapeutic administration on days 10-20 was also effective, and inhi bition of paw edema was observed at 60, 30, and 10 mg/kg (73%, 51%, and 19% , respectively). Significant improvement in joint integrity was demonstrate d by showing normalization of BMD and also by MRI and micro-CT analysis. Pr otection of bone, cartilage, and soft tissues was also shown histologically . Serum IL-6 levels were decreased in AIA rats treated with the 60 mg/kg do se of compound. Conclusion, Symptoms of AZA in rats were significantly reduced by both prop hylactic and therapeutic treatment with the p38 MAP kinase inhibitor, SE 24 2235, Results from measurements of paw inflammation, assessment of BMD, MRT , and micro-CT indicate that this compound exerts a protective effect on jo int integrity, and thus appears to have disease-modifying properties.