Adenosine (
ADO) is a homeostatic inhibitory autocoid that is released at sites of
inflammation and tissue injury, and exerts anti-inflammatory effects via multiple interactions at
ADO receptor subtypes. Inhibition of
ADO kinase (AK) increases extracellular
ADO concentrations and AK inhibitors have demonstrated
ADO-mediated anti-inflammatory effects in acute models of
inflammation. To evaluate the potential utility of this approach in chronic
inflammation, a novel, potent, and selective non-
nucleoside AK inhibitor,
ABT-702, 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
ABT-702 (20 mg/kg/b.i.d. p.o.) beginning on day 8.
ABT-702 significantly inhibited
arthritis as determined by paw volume. In addition, histologic and radiographic evidence of bone and cartilage destruction was significantly decreased in the treated group. Coadministration of the
ADO receptor antagonist
theophylline attenuated the anti-inflammatory effects of
ABT-702, suggesting that this action was mediated through endogenous
ADO release. To evaluate the mechanism of chondroprotection, Northern blot and electrophoretic mobility shift assays were performed on joints samples. These studies demonstrated 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 clinical, radiographic, and histologic evidence of chronic inflammatory
arthritis. The mechanism of joint protection is likely related to suppressed
transcription factor activation and
matrix metalloproteinase gene expression.