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 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-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 antiinflammatory 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.

Control of Gut Inflammation by Modulation of Purinergic Signaling

“…Preliminary experiments conducted in rat ileum/jejunum preparations showed a significant improvement of the impaired acetylcholine-induced contractions and this beneficial effect was boosted by A2BR selective antagonists (52). Importantly, administration of this compound in a rat model of oxazolone-induced colitis limited weight loss and decreased levels of TNF-α in colonic tissue (53).…”

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

“…Systemic administration of the selective A 2A receptor agonist CGS21680 was, however, not protective in mice with DSS-induced colitis (Selmeczy et al, 2007). In contrast, oral administration of the poorly absorbed A 2A receptor agonist PSB-0777 was anti-inflammatory and protective in a rat model of oxazolone-induced colitis (Antonioli et al, 2018). Thus, the systemic effects of A 2A receptor stimulation may offset its local protective effects.…”

“…In addition to the "classical" pro-and anti-inflammatory mediators described above, purines are emerging as powerful extracellular signaling molecules, which orchestrate the onset, magnitude duration, and resolution of the inflammatory response through the activation of purinergic receptors, which are widely expressed on most cell types involved in inflammatory processes (Hasko et al, 1996(Hasko et al, , 1998(Hasko et al, , 2000a(Hasko et al, ,b, 2008(Hasko et al, , 2011Nemeth et al, 2005Nemeth et al, , 2006Nemeth et al, , 2007Csóka et al, 2008Csóka et al, , 2010Csóka et al, , 2012Csóka et al, , 2015aCsóka et al, ,b, 2018Ramanathan et al, 2009;Himer et al, 2010;Hasko and Pacher, 2012;Koscso et al, 2013;Burnstock and Boeynaems, 2014;Antonioli et al, 2018). Alterations in the purinergic machinery are a common contributory factor to the pathophysiological processes underlying the onset and development of IMIDs.…”

Inflammatory Bowel Diseases: It's Time for the Adenosine System

“…The pharmacological activation of A 2A receptors, via inosine administration, has exerted beneficial effects in animals with colitis induced by TNBS, indicating the A 2A receptor activation as an intriguing pharmacological strategy for management of gut inflammation (22). Likewise, oral administration of PSB-0777, a scarcely absorbed A 2A receptor agonist, alleviated bowel inflammation in oxazolone-induced colitis rats (23). However, treatment with CGS21680, a recognized selective A 2A receptor agonist failed in ameliorating a murine model of DSS-induced colitis (24).…”