Anti-inflammatory effect of a novel locally acting A2A receptor agonist in a rat model of oxazolone-induced colitis

Abstract

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 A₁, A_2A, A_2B, and A₃, 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-γ 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.

Keywords: A2A adenosine receptor; Colitis; Colon; Inflammation; Locally acting agent.

Fig. 1

Diagram showing the design and time course of experiments on rats with oxazolone-induced colitis

Fig. 2

Chemical structure of PSB-0777

Fig. 3

Effects of PSB-0777 (0.4 mg/kg/day) alone or in combination with CSC (1 mg/kg/day) or dexamethasone (1 mg/kg/day) on body weight in rats with oxazolone-induced colitis. Each column represents the mean ± S.E.M (n = 6). *p < 0.05, significant difference versus control group; ^a p < 0.05, significant difference versus oxazolone group

Fig. 4

Hematoxylin and eosin-stained sections of rat colon. Microscopic images refer to control rats (a) or oxazolone-treated animals, either alone (b) or in the presence of PSB-0777 (0.4 mg/kg/day) (c) or dexamethasone (1 mg/kg/day) (d)

Fig. 5

Microscopic damage scores estimated for colon in rats under normal conditions or after oxazolone treatment, either alone or in the presence of PSB-0777 (0.4 mg/kg/day) alone or in combination with CSC (1 mg/kg/day), or dexamethasone (1 mg/kg/day) administration. Each column represents the mean S.E.M. (n = 6). *p < 0.05, significant difference versus control group; ^a p < 0.05, significant difference versus oxazolone group

Fig. 6

a MPO and b TNF levels in colonic tissues from control rats or in animals treated with oxazolone, either alone or in combination with PSB-0777 (0.4 mg/kg/day) alone or in combination with CSC (1 mg/kg/day), or dexamethasone (1 mg/kg/day). Each column represents the mean S.E.M. (n = 6). *p < 0.05, significant difference versus control group; ^a p < 0.05, significant difference versus oxazolone group

Fig. 7

a Plasma concentration of PSB-0777 (0.4 mg/kg/day) 30, 60, 120, and 240 min after oral or intraperitoneal administration in rats with oxazolone-induced colitis. b Effects of PSB-0777(0.4 mg/kg/day) 30, 60, 120, 240 min after oral or intraperitoneal administration on systolic blood pressure in rats with oxazolone-induced colitis. Each column represents the mean S.E.M. (n = 6). *p < 0.05, significant difference versus vehicle-treated animals