Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models

• Published in: Journal of rheumatology 2005-03, Vol.32 (3), p.469-476
• Main Authors: BAHARAV, Ehud, BAR-YEHUDA, Sara, MADI, Lea, SILBERMAN, Daniel, RATH-WOLFSON, Lea, HALPREN, Marisa, OCHAION, Avivit, WEINBERGER, Abraham, FISHMAN, Pnina
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosine - therapeutic use; Adenosine A3 Receptor Agonists; Adenosine A3 Receptor Antagonists; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Arthritis, Experimental - drug therapy; Arthritis, Experimental - pathology; Bacterial arthritis and osteitis; Bacterial diseases; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Collagen - immunology; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Female; Human bacterial diseases; Infectious diseases; Joints - drug effects; Joints - immunology; Joints - pathology; Lymph Nodes - immunology; Male; Medical sciences; Mice; Mice, Inbred DBA; Miscellaneous. Osteoarticular involvement in other diseases; Pharmacology. Drug treatments; Quinazolines - pharmacology; Rats; Receptor, Adenosine A3 - metabolism; Spleen - immunology; Triazoles - pharmacology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0315-162X; 1499-2752

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-alpha (TNF-alpha). 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-alpha 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-alpha 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-alpha production. The beneficial activity of the drugs at the low dose demonstrates that the effect is A3AR mediated.