Inhibition of adenosine deaminase attenuates inflammation in experimental colitis.
Adenosine modulates the immune system and inhibits inflammation via reduction of cytokine biosynthesis and neutrophil functions. Drugs able to prevent adenosine catabolism could represent an innovative strategy to treat inflammatory bowel disorders. In this study, the effects of 4-amino-2-(2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP; novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA; standard adenosine deaminase inhibitor), and dexamethasone were tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid (DNBS). DNBS-treated animals received APP (5, 15, or 45 micromol/kg), EHNA (10, 30, or 90 micromol/kg), or dexamethasone (0.25 micromol/kg) i.p. for 7 days starting 1 day before colitis induction. DNBS caused bowel inflammation associated with decrease in food intake and body weight. Animals treated with APP or EHNA, but not dexamethasone, displayed greater food intake and weight gain than inflamed rats. Colitis induced increment in spleen weight, which was counteracted by all test drugs. DNBS administration was followed by macroscopic and microscopic inflammatory colonic alterations, which were ameliorated by APP, EHNA, or dexamethasone. In DNBS-treated rats, colonic myeloperoxidase, malondialdehyde, and tumor necrosis factor (TNF)-alpha levels as well as plasma TNF-alpha and interleukin-6 were increased. All test drugs lowered these phlogistic indexes. Inflamed colonic tissues displayed an increment of inducible nitric-oxide synthase mRNA, which was unaffected by APP or EHNA, but reduced by dexamethasone. Cyclooxygenase-2 expression was unaffected by DNBS or test drugs. These findings indicate that 1) inhibition of adenosine deaminase results in a significant attenuation of intestinal inflammation and 2) the novel compound APP is more effective than EHNA in reducing systemic and intestinal inflammatory alterations.
Antonioli
Luca
L
Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Pisa, Italy.
Fornai
Matteo
M
Colucci
Rocchina
R
Ghisu
Narcisa
N
Da Settimo
Federico
F
Natale
Gianfranco
G
Kastsiuchenka
Olga
O
Duranti
Emiliano
E
Virdis
Agostino
A
Vassalle
Cristina
C
La Motta
Concettina
C
Mugnaini
Laura
L
Breschi
Maria Cristina
MC
Blandizzi
Corrado
C
Del Taca
Mario
M
D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000243:Adenosine Deaminase / Q000737:chemistry; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001557:Benzenesulfonates / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
C503894:2-(2-hydroxydecyl)-4-aminopyrazolo(3,4-d)pyrimidine; D058892:Adenosine Deaminase Inhibitors; D001557:Benzenesulfonates; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D011720:Pyrazoles; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; C001073:2,4-dinitrobenzenesulfonic acid; D008315:Malondialdehyde; C010192:9-(2-hydroxy-3-nonyl)adenine; D003907:Dexamethasone; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D000243:Adenosine Deaminase; D000225:Adenine