The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-κB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats

The A(3) adenosine receptor (A(3)AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant-and collagen-induced arthritis. In this study we present a novel A(3)AR agonist, CF502, with high affinity and selectivity at the human A(3)AR. CFS02 induced a dose dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes (FLS) via de-regulation of the nuclear factor-kappa B (NF-kappa B) signaling pathway. Furthermore, CF502 markedly suppressed the clinical and pathological manifestations of adjuvant- induced arthritis (AIA) in a rat experimental model when given orally at a low dose (100 mu g/kg). As is typical of other G-protein coupled receptors, the A(3)AR expression level was down-regulated shortly after treatment with agonist CF502 in paw and in peripheral blood mononuclear cells (PBMCs) derived from treated AIA animals. Subsequently, a decrease in the expression levels of protein kinase B/Akt (PKB/Akt), I kappa B kinase (IKK), I kappa B (I kappa B), NF-kappa B and tumor necrosis factor-alpha (TNF-alpha) took place. in addition, the expression levels of glycogen synthase kinase-3 beta (GSK-3 beta), beta-catenin, and poly(ADP-ribose)polymerase (PARP), known to control the level and activity of NF-kappa B, were down-regulated upon treatment with CF502. Taken together, CF502 inhibits FLS growth and the inflammatory manifestations of arthritis, supporting the development of A3AR agonists; for the treatment of rheumatoid arthritis. (C) 2008 Elsevier Inc. All rights reserved.