Purinergic Ligands as Potential Therapeutic Tools for the Treatment of Inflammation-Related Intestinal Diseases

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.

Electroacupuncture inhibits visceral pain via adenosine receptors in mice with inflammatory bowel disease

“…*P < 0.05, compared with the control group; # P < 0.05, compared with the TNBS group; △ P < 0.05, compared with the TNBS+EA group [39]. The A2aR agonist can act as a pharmacological tool to manage IBD, and the antagonist can be used to treat functional dyspepsia [40]. Furthermore, A2a receptor antagonists can reverse the function of adenosine (0.3-100 mg/kg, i.p.)…”

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

“…In particular, adenosine and its receptors demonstrated a profound reorganization in the inflammatory contexts, taking a significant part in shaping the immune responses (17). On these premises, several studies investigated the therapeutic potential of ligands acting on the adenosine system in the management of intestinal inflammation (17). However, a critical evaluation of the available pre-clinical studies about the efficacy of drugs acting on the adenosine system in managing the chronic inflammatory bowel diseases, is complicated by the heterogeneity of the in vivo and in vitro models employed, which could lead, in some cases, to conflicting results.…”

“…In this context, the evaluation about the involvement of adenosine pathways in the pathophysiology of enteric dysmotility associated with IBDs, has become an area of active investigation (1,74,75). Several evidences highlighted a marked reorganization of adenosine receptor expression and activity in the presence of intestinal inflammation (1,17,74,75). Different murine model of chronic bowel inflammation revealed a reduced modulatory role by A 1 receptors in the small and large bowel (76,77).…”

Non-Nucleoside Agonists of the Adenosine Receptors: An Overview

“…Modulation of further second messengers has also been described, which involves the activation of signaling mechanisms like phospholipase C, Protein Kinase C (PKC), phosphoinositide 3-kinases, ion channels, and the modulation of calcium levels [1,3,4]. The stimulation of the various AR subtypes has effects on Central Nervous System (CNS) and peripheral tissues [5,6], modulating release of neurotransmitters, synaptic transmission [7], heart rate and atrial contractility, vascular smooth muscle tone [8], gastrointestinal functions [9,10], as well as renal [11], platelet [12], and leukocyte [13] functions. Therefore, AR regulation represents a high-potential strategy for the development of therapeutic tools.…”