1. The blockade of adenosine deaminase ameliorates chronic experimental colitis through the recruitment of adenosine A2A and A3 receptors.
- Author
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Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, Tuccori M, Da Settimo F, La Motta C, Natale G, Duranti E, Virdis A, and Blandizzi C
- Subjects
- Adenine pharmacology, Adenine therapeutic use, Adenosine Deaminase biosynthesis, Animals, Blotting, Western, Body Weight drug effects, Chronic Disease, Colitis enzymology, Colitis immunology, Colitis metabolism, Colon drug effects, Colon enzymology, Colon immunology, Colon metabolism, Cytokines immunology, Disease Models, Animal, Enzyme Inhibitors pharmacology, Male, Organ Size drug effects, Pyrazoles pharmacology, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Adenine analogs & derivatives, Adenosine Deaminase Inhibitors, Colitis prevention & control, Enzyme Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A3 metabolism
- Abstract
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 after adenosine deaminase blockade. Adenosine deaminase expression was determined by Western blot. The effects of 4-amino-2-(2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP; a novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; a 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, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA)] inflammatory parameters were assessed. Test drugs were administered intraperitoneally 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 MDA. 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, and MDA levels. The beneficial effects of APP and EHNA on inflammatory parameters were prevented by the pharmacological blockade of A(2A) or A(3) receptors, but not A(1) or A(2B). The present results show that: 1) bowel inflammation is associated with an enhanced adenosine deaminase expression; and 2) the anti-inflammatory actions of adenosine deaminase inhibitors against chronic established colitis depend on the sparing of endogenous adenosine, leading to enhanced A(2A) and A(3) receptor activation.
- Published
- 2010
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