The blockade of adenosine deaminase ameliorates chronic experimental colitis through the recruitment of adenosine A2A and A3 receptors.

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.

• Authors: Luca Antonioli, Matteo Fornai, Rocchina Colucci, Oriana Awwad, Narcisa Ghisu, Marco Tuccori, Federico Da Settimo, Concettina La Motta, Gianfranco Natale, Emiliano Duranti, Agostino Virdis, Corrado Blandizzi
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 335 Issue 2 Pg. 434-42 (Nov 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20668053 (Publication Type: Journal Article)

Chemical References

• 2-(2-hydroxydecyl)-4-aminopyrazolo(3,4-d)pyrimidine
• Adenosine Deaminase Inhibitors
• Cytokines
• Enzyme Inhibitors
• Pyrazoles
• Pyrimidines
• Receptor, Adenosine A2A
• Receptor, Adenosine A3
• 9-(2-hydroxy-3-nonyl)adenine
• Adenosine Deaminase
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology, therapeutic use)
• Adenosine Deaminase (biosynthesis)
• Adenosine Deaminase Inhibitors
• Animals
• Blotting, Western
• Body Weight (drug effects)
• Chronic Disease
• Colitis (enzymology, immunology, metabolism, prevention & control)
• Colon (drug effects, enzymology, immunology, metabolism)
• Cytokines (immunology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Male
• Organ Size (drug effects)
• Pyrazoles (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Adenosine A2A (metabolism)
• Receptor, Adenosine A3 (metabolism)