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Antiinflammatory Effect of A3 Adenosine Receptor Agonists in Murine Autoimmune Arthritis Models
EHUD BAHARAV, SARA BAR-YEHUDA, LEA MADI, DANIEL SILBERMAN, LEA RATH-WOLFSON, MARISA HALPREN, AVIVIT OCHAION, ABRAHAM WEINBERGER, and PNINA FISHMAN
ABSTRACT. Objective. CF101, an A3 adenosine receptor (A3AR) agonist, is a small orally bioavailable molecule known to suppress in vitro the production of tumor necrosis factor-a (TNF-a). We evaluated its therapeutic potential and antiinflammatory effects in 3 murine models of adjuvant induced arthritis (AIA). Methods. The antiinflammatory effect of CF101 was examined in rat AIA, in mouse collagen induced arthritis, and in tropomyosin induced arthritis. The clinical effect of another A3AR agonist, Cl-IB-MECA, was examined in rat AIA. The effect of low dose (10 or 100 mg/kg/day) A3AR agonists administered orally once daily on arthritis severity was assessed clinically and histologically. The effect of CF101 on the protein expression level of TNF-a in the synovial tissue, draining lymph nodes, and spleen cells was determined by Western blot. Results. CF101 and Cl-IB-MECA markedly ameliorated the clinical and histological features of arthritis in the 3 models when administered orally at a low dose of 10 mg/kg body weight in the 3 autoimmune arthritis models. The lower dose of 10 mg/kg of either CF101 or Cl-IB-MECA had better antiinflammatory effect than the higher 100 mg/kg dose. Decreased expression of TNF-a was noted in protein extracts of synovia, draining lymph nodes, and spleen tissues. Conclusion. The results provide evidence that A3AR agonists exert significant antirheumatic effects in different autoimmune arthritis models by suppression of TNF-a production. The beneficial activity of the drugs at the low dose demonstrates that the effect is A3AR mediated. (J Rheumatol 2005;32:469–76) Key Indexing Terms:
A3 ADENOSINE RECEPTOR AGONIST
From Can-Fite BioPharma Ltd., Kiryat-Matalon, Petach-Tikva; Department of Medicine B, Beilinson Campus, Laboratory of Joints Physiopathology, Felsenstein Medical Research Center; Laboratory of Clinical and Tumor Immunology, Felsenstein Medical Research Center, Tel-Aviv University Sackler Faculty of Medicine, Rabin Medical Center; Department of Pathology, Golda Campus, Rabin Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. E. Baharav, MD, Can-Fite BioPharma Ltd. and Laboratory of Joints Physiopathology, Felsenstein Medical Research Center; S. Bar-Yehuda, PhD, Can-Fite BioPharma Ltd. and Laboratory of Clinical and Tumor Immunology, Felsenstein Medical Research Center; L. Madi, PhD; D. Silberman, VetD, Can-Fite BioPharma Ltd.; L. Rath-Wolfson, MD; M. Halpren, MD, Department of Pathology, Rabin Medical Center and Sackler Faculty of Medicine, Tel Aviv University; A. Weinberger, MD, Laboratory of Joints Physiopathology, Felsenstein Medical Research Center; P. Fishman, PhD, Can-Fite BioPharma Ltd. and Laboratory of Clinical and Tumor Immunology, Felsenstein Medical Research Center. Address reprint requests to Prof. P. Fishman, Can-Fite Bio Pharma Ltd., 10 Bareket Street, Kiryat-Matalon, Petach-Tikva, Israel 49170. E-mail: pfishman@post.tau.ac.il Submitted September 3, 2004; revision accepted October 13, 2004. |