Adenosine modulates immune/inflammatory reactions. This study investigates the expression of adenosine deaminase in the inflamed colon, the effects of adenosine deaminase inhibitors on established colitis and the recruitment of adenosine receptors by endogenous adenosine following adenosine deaminase blockade.Adenosine deaminase expression was determined by Western blot. The effects of 4-amine-2-(2-hydroxy 1-decyl)pyrazole[3,4-d]pyrimidine(APP, novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, reference adenosine deaminase inhibitor), dexamethasone and selective adenosine receptor antagonists were tested in rats with 2,4-dinitrobenzenesulfonic acid-induced colitis. Systemic (food intake, body and spleen weight) and colonic (macroscopic/microscopic damage, TNF-α, IL-6 and malondialdehyde) inflammatory parameters were assessed. Test drugs were administered i.p. for 6 days, starting at day 5 from colitis induction. Adenosine deaminase was detected in normal colon, and its expression was increased in inflamed tissues. Colitis was associated with decreased food intake and body weight, augmented spleen weight, and increased levels of colonic TNF-α, IL-6 and malondialdehyde. APP or EHNA, but not dexamethasone, improved food intake and body weight. APP, EHNA and dexamethasone counteracted the increments of spleen weight, ameliorated macroscopic and microscopic indexes of inflammation, and reduced TNF-α, IL-6 levels and malondialdehyde. The beneficial effects of APP and EHNA on inflammatory parameters were prevented by the pharmacological blockade of A2A or A3 receptors, but not A1 or A2B. The present results show that: a) bowel inflammation is associated with an enhanced adenosine deaminase expression; b) the anti-inflammatory actions of adenosine deaminase inhibitors against chronic established colitis depend on sparing of endogenous adenosine leading to enhanced A2A and A3 receptor activation.
- The American Society for Pharmacology and Experimental Therapeutics