The blockade of adenosine deaminase ameliorates chronic experimental colitis through the recruitment of adenosine A2A and A3 receptors.
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.
Antonioli
Luca
L
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Fornai
Matteo
M
Colucci
Rocchina
R
Awwad
Oriana
O
Ghisu
Narcisa
N
Tuccori
Marco
M
Da Settimo
Federico
F
La Motta
Concettina
C
Natale
Gianfranco
G
Duranti
Emiliano
E
Virdis
Agostino
A
Blandizzi
Corrado
C
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000243:Adenosine Deaminase / Q000096:biosynthesis; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D003092:Colitis / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043684:Receptor, Adenosine A3 / Q000378:metabolism*
C503894:2-(2-hydroxydecyl)-4-aminopyrazolo(3,4-d)pyrimidine; D058892:Adenosine Deaminase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; C010192:9-(2-hydroxy-3-nonyl)adenine; D000243:Adenosine Deaminase; D000225:Adenine