Anti-inflammatory effect of a novel locally acting A(2A) receptor agonist in a rat model of oxazolone-induced colitis

Adenosine represents a powerful modulating factor, which has been shown to orchestrate the scope, duration, and remission of the inflammatory response through the activation of four specific receptors, classified as A(1), A(2A), A(2B), and A(3), all being widely expressed in a variety of immune cells. Several selective A(2A) receptor agonists have displayed anti-inflammatory effects, through the suppression of IL-12, TNF, and IFN-gamma production by monocytes and lymphocytes, in the setting of chronic intestinal inflammation. However, the therapeutic application of A(2A) receptor agonists remains hindered by the risk of serious cardiovascular adverse effects arising from the wide systemic distribution of A(2A) receptors. The present study focused on evaluating the anti-inflammatory effects of the novel poorly absorbed A(2A) receptor agonist PSB-0777 in a rat model of oxazolone-induced colitis as well as to evaluate its cardiovascular adverse effects, paying particular attention to the onset of hypotension, one of the main adverse effects associated with the systemic pharmacological activation of A(2A) receptors. Colitis was associated with decreased body weight, an enhanced microscopic damage score and increased levels of colonic myeloperoxidase (MPO). PSB-0777, but not dexamethasone, improved body weight. PSB-0777 and dexamethasone ameliorated microscopic indexes of inflammation and reduced MPO levels. The beneficial effects of PSB-0777 on inflammatory parameters were prevented by the pharmacological blockade of A(2A) receptors. No adverse cardiovascular events were observed upon PSB-0777 administration. The novel A(2A) receptor agonist PSB-0777 could represent the base for the development of innovative pharmacological entities able to act in an event-specific and site-specific manner.