Selective adenosine A2A receptor agonist, ATL-146e, attenuates stress-induced gastric lesions in rats

Background: Activation of adenosine A(2A) receptors reduces the production of various pro-inflammatory cytokines and suppresses neutrophil activation. Water-immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress-induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A2A receptors are known to be anti-inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A2A receptor agonist, ATL-146e, on water-immersion stress-induced gastric mucosal lesions was studied. Methods: Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of a potent and selective agonist of the adenosine A2A receptor. The gastric concentrations of myeloperoxidase (MPO), as an index of neutrophil accumulation, and the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), were measured. Results: The total length of gastric erosions (ulcer index) in control rats was 21.6 +/- 3.23 mm and was reduced by 86% to 3.1 +/- 0.83 mm by pretreatment with 5.0 mu g/kg ATL146e (P <0.001). The gastric content of MPO, TNF-alpha and IL-1 beta were all increased after water-immersion stress and reduced to near normal levels by ATL-146e. Conclusion: A specific adenosine A2A agonist inhibits stress-induced gastric inflammation and damage. A2A agonist compounds may be useful for preventing ulcers and appear to act by blocking gastric inflammation. (C) 2004 Blackwell Publishing Asia Pty Ltd.