title: Effect of novel A2A adenosine receptor agonist ATL 313 on Clostridium difficile toxin A-induced murine ileal enteritis.
abstract: Clostridium difficile is a spore-forming, anaerobic, gram-positive bacillus that releases two main virulence factors: toxins A and B. Toxin A plays an important pathogenic role in antibiotic-induced diarrhea and pseudomembranous colitis, a condition characterized by intense mucosal inflammation and secretion. Agonist activity at A2A adenosine receptors attenuates inflammation and damage in many tissues. This study evaluated the effects of a new selective A2A adenosine receptor agonist (ATL 313) on toxin A-induced injury in murine ileal loops. ATL 313 (0.5 to 5 nM) and/or the A2A adenosine receptor antagonist (ZM241385; 5 nM) or phosphate-buffered saline (PBS) were injected into ileal loops immediately prior to challenge with toxin A (1 to 10 microg/loop) or PBS. Intestinal fluid volume/length and weight/length ratios were calculated 3 h later. Ileal tissues were collected for the measurement of myeloperoxidase, adenosine deaminase activity, tumor necrosis factor alpha (TNF-alpha) production, histopathology, and detection of cell death by the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) method. Toxin A significantly increased volume/length and weight/length ratios in a dose-dependent fashion. ATL 313 treatment significantly (P < 0.05) reduced toxin A-induced secretion and edema, prevented mucosal disruption, and neutrophil infiltration as measured by myeloperoxidase activity. ATL 313 also reduced the toxin A-induced TNF-alpha production and adenosine deaminase activity and prevented toxin A-induced cell death. These protective effects of ATL 313 were reversed by ZM241385. In conclusion, the A2A adenosine receptor agonist, ATL 313, reduces tissue injury and inflammation in mice with toxin A-induced enteritis. The finding of increased ileal adenosine deaminase activity following the administration of toxin A is new and might contribute to the pathogenesis of the toxin A-induced enteritis by deaminating endogenous adenosine.
authors.affiliation: Faculdade de Medicina, Universidade Federal do Ceará, Rua Delmiro de Farias, sn CEP 60.416-030, Fortaleza, CE, Brazil.
authors.forename: I C
authors.initials: IC
authors.lastname: Cavalcante
authors.forename: M V
authors.initials: MV
authors.lastname: Castro
authors.forename: A R F
authors.initials: AR
authors.lastname: Barreto
authors.forename: G W
authors.initials: GW
authors.lastname: Sullivan
authors.forename: M
authors.initials: M
authors.lastname: Vale
authors.forename: P R C
authors.initials: PR
authors.lastname: Almeida
authors.forename: J
authors.initials: J
authors.lastname: Linden
authors.forename: J M
authors.initials: JM
authors.lastname: Rieger
authors.forename: F Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: R L
authors.initials: RL
authors.lastname: Guerrant
authors.forename: R A
authors.initials: RA
authors.lastname: Ribeiro
authors.forename: G A C
authors.initials: GA
authors.lastname: Brito
mesh_terms: D058908:Adenosine A2 Receptor Agonists; D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000633:toxicity*; D004751:Enteritis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004768:Enterotoxins / Q000633:toxicity*; D007077:Ileal Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007082:Ileum / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D001427:Bacterial Toxins; D004768:Enterotoxins; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; C041348:tcdA protein, Clostridium difficile; D000243:Adenosine Deaminase