Anti-inflammatory effects of ABT-702, a novel non-nucleoside adenosine kinase inhibitor, in rat adjuvant arthritis

Adenosine (ADO) is a homeostatic inhibitory autocoid that is released at si tes of inflammation and tissue injury, and exerts anti-inflammatory effects via multiple interactions at ADO receptor subtypes. Inhibition of ADO kina se (AK) increases extracellular ADO concentrations and AK inhibitors have d emonstrated ADO-mediated anti-inflammatory effects in acute models of infla mmation. To evaluate the potential utility of this approach in chronic infl ammation, a novel, potent, and selective non-nucleoside AK inhibitor, ABT-7 02, was tested in the rat adjuvant arthritis model. Animals were immunized with complete Freund's adjuvant on day 0 and were treated with vehicle or A BT-702 (20 mg/kg/b.i.d. p.o.) beginning on day 8. ABT-702 significantly inh ibited arthritis as determined by paw volume. In addition, histologic and r adiographic evidence of bone and cartilage destruction was significantly de creased in the treated group. Coadministration of the ADO receptor antagoni st theophylline attenuated the anti-inflammatory effects of ABT-702, sugges ting that this action was mediated through endogenous ADO release. To evalu ate the mechanism of chondroprotection, Northern blot and electrophoretic m obility shift assays were performed on joints samples. These studies demons trated that ABT-702 suppressed collagenase and stromelysin gene expression in treated animals. In addition, the activator protein-1 and nuclear factor -kappaB binding activity was also decreased. Therefore, ABT-702 inhibited c linical, radiographic, and histologic evidence of chronic inflammatory arth ritis. The mechanism of joint protection is likely related to suppressed tr anscription factor activation and matrix metalloproteinase gene expression.