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


CONCLUSIONS
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.
Baharav
Ehud
E
Can-Fite BioPharma Ltd., 10 Bareket Street, Kiryat-Matalon, Petach-Tikva, Tel Aviv, Israel 49170.
Bar-Yehuda
Sara
S
Madi
Lea
L
Silberman
Daniel
D
Rath-Wolfson
Lea
L
Halpren
Marisa
M
Ochaion
Avivit
A
Weinberger
Abraham
A
Fishman
Pnina
P
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D003094:Collagen / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007596:Joints / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000893:Anti-Inflammatory Agents; C478920:CF101; D011799:Quinazolines; D043684:Receptor, Adenosine A3; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D000241:Adenosine