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 A2A or A3 receptors, but not A1 or A2B. 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 A2A and A3 receptor activation.
Footnotes
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The results of this work were presented previously as an oral communication: Fornai R, Antonioli L, Colucci R, Ghisu N, Da Settimo F, La Motta C, Natale G, Kastsiuchenka O, Duranti E, Virdis A, Del Tacca M, and Blandizzi C (2009) Mechanisms underlying the anti-inflammatory effects of adenosine deaminase inhibitors in experimental colitis. Digestive Disease Week 2009; 2009 May 30–June 4; Chicago, IL. American Gastroenterological Association Institute, Bethesda, MD.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.171223.
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ABBREVIATIONS:
- IBD
- inflammatory bowel disease
- APP
- 4-amino-2-(2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine
- CSC
- 8-(3-chlorostyryl) caffeine
- DNBS
- 2,4-dinitrobenzenesulfonic acid
- EHNA
- erythro-9-(2-hydroxy-3-nonyl)adenine
- IL-6
- interleukin-6
- MDA
- malondialdehyde
- MPO
- myeloperoxidase
- TNF-α
- tumor necrosis factor-α
- MRS 1191
- 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate
- MRS 1754
- N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]-acetamide
- PBS-T
- Tween 20 phosphate-buffered saline
- DPCPX
- 8-cyclopentyl-1,3-dipropylxanthine.
- Received June 9, 2010.
- Accepted July 27, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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