Abstract
Inflammation-related intestinal diseases are a set of various conditions presenting an overactive enteric immune system. A continuous overproduction of pro-inflammatory cytokines and a decreased production of anti-inflammatory modulators are generally observed, while morpho-functional alterations of the enteric nervous system lead to intestinal secretory and motor dysfunctions. The factors at the basis of these conditions are still to be totally identified and current therapeutic strategies are aimed only at achieving and maintaining remission states, by using therapeutic tools like aminosalicylates, corticosteroids, immunomodulators, biological drugs (i.e., monoclonal antibodies), and eventually surgery. Recent reports described a key role of purinergic mediators (i.e., adenosine and its nucleotides ATP and ADP) in the regulation of the activity of immune cells and enteric nervous system, showing also that alterations of the purinergic signaling are linked to pathological conditions of the intestinal tract. These data prompted to a series of investigations to test the therapeutic potential for inflammation-related intestinal conditions of compounds able to restore or modulate an altered purinergic signaling within the gut. This review provides an overview on these investigations, describing the results of preclinical and/or clinical evaluation of compounds able to stimulate or inhibit specific P2 (i.e., P2X7) or P1 (i.e., A2A or A3) receptor signaling and to modify the adenosine levels through the modulation of enzymes activity (i.e., Adenosine Deaminase) or nucleoside transporters. Recent developments in the field are also reported and the most promising purine-based therapeutic strategies for the treatment of inflammation-related gastrointestinal disorders are schematically summarized.
Highlights
Inflammatory bowel diseases (IBDs) comprise Crohn’s disease and ulcerative colitis and are conditions presenting an overactive intestinal immune system
The lack in change of inflammatory parameters, this study demonstrated that AZD9056 has the potential to improve symptoms, in particular abdominal pain, in patients with IBDs (Eser et al, 2015)
Several authors investigated the efficacy of pharmacological treatments aimed at increasing the levels of endogenous adenosine, through the blockade of pivotal catabolic enzymes, as an alternative way to counteract intestinal inflammation. Extracellular ATP (eATP) is rapidly degraded to adenosine by ectonucleotidases CD73 and CD39
Summary
Inflammatory bowel diseases (IBDs) comprise Crohn’s disease and ulcerative colitis and are conditions presenting an overactive intestinal immune system. Focusing on the bowel-related conditions, Grbic et al (2008), investigating the role of ATP receptors in the pathogenesis of intestinal inflammation, reported that the pro-inflammatory cytokines TNF-α or IFN-γ determined an increased expression of P2Y2 and P2Y6 receptors in the colonic mucosa of mice with DSS colitis (Grbic et al, 2008; Degagne et al, 2013). Stimulation of the P2Y6R led to the activation of calcium-independent PKCδ upstream of ERK1/2, followed by the stimulation of c-fos phosphorylation and the recruitment of c-fos/c-jun dimers at level of the AP-1 motif located within the core promoter region of IL-8 gene, determining an increase of IL-8 release (Grbic et al, 2012) Despite these encouraging results, further investigations are needed to evaluate the putative beneficial effect of P2Y2 and P2Y6 receptor ligands in counteracting intestinal inflammation. It has been demonstrated that the reduction of A2AAR in the digestive tract of aged mice, contributes to an increased inflammation and lower ability to FIGURE 1 | Schematic figure with the putative contribution of the main purinergic signals (ATP and adenosine) and their different receptors (P2X3, P2X7, P2Y1,2,6, A2A, and A3) in different cell types of the intestinal tract
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
