(C) Abundance of CD4+cells in 1.5% DSS colitis. == Functional disruption of A3AR in A3/AR mice alters intestinal motility. We postulate that ongoing release of adenosine and activation of presynaptic-inhibitory A3AR can slow down transit and inhibit the defecation reflex. A3AR may be involved in gliotransmission. In separate studies, A3/AR protects against DSS-colitis consistent with a novel hypothesis that A3AR activation contributes to development of colitis. Keywords:Murine DSS-Colitis, A3/AR mouse, Adenosine Receptors, Motility, Presynaptic inhibitory A3AR, gliotransmission, Enteric Nervous System == INTRODUCTION == Activation of adenosine A1, A2A, A2Band A3receptors is involved in the modulation of enteric neural reflexes1. Adenosine (ADO) A1, A2and A3receptor (A3AR) proteins or mRNA exist in rodent2and human intestinal tract3. Receptors are differentially expressed in neural and non-neural cells of the gut. Functional evidence for A1 inhibitory, non-A1 (putative A3AR) and A2excitatory receptors exists for rodent enteric neurons1,4. Endogenous adenosine (eADO) release inhibits 5-HT release from enterochromaffin cells (EC), and suppresses neuronal excitability and synaptic transmission in the enteric nervous system (ENS) by activating high affinity A1AR, and perhaps low affinity A3AR. Low oxygen tension is a potent stimulus Talabostat mesylate for eADO release to suppress peptidergic neurotransmission in networks of enteric ganglia5. In human EC or intact networks of human ENS submucous ganglia, functional inhibitory A3AR can be revealed by selective A3agonists like N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (IB-MECA) or 2-Cl-IB-MECA, and effects of A3AR antagonists alone suggest that eADO levels are sufficient to activate low affinity A3AR6,7. It Rabbit Polyclonal to EHHADH has been postulated that high affinity inhibitory A1AR are involved in physiological regulation whereas low affinity inhibitory A3AR are more likely to be activated by eADO in pathophysiological states because they require high levels of eADO to Talabostat mesylate activate them that are more easily achieved in disease states812. Recent studies are beginning to unravel possible beneficial effects of elevating extracellular levels of eADO1416or activation of A3AR17,18, A2AAR1922or A2BAR23in models of inflammatory bowel diseases (IBD) with drug agonists or antagonists depending on the receptor. Increasing the concentration of eADO is one mechanism by which several drugs may reduce Talabostat mesylate gut inflammation1416. Chronic administration of an adenosine kinase inhibitor15,16or an A3 agonist IB-MECA17may be beneficial in murine models of dextran sodium sulfate (DSS) induced colitis or a rat trinitrobenzene-sulfonic acid (TNBS) induced colitis model18, but the mechanisms or receptors involved remain poorly understood. IB-MECA is well tolerated orally by healthy human volunteers24and has been in Phase IIb clinical trials for another chronic inflammatory disease, rheumatoid arthritis, and is without apparent toxicity (www.canfite.com/develop.html). The prototypical A3AR agonist IB-MECA has been shown to have protective effects in rodent models of colitis (DSS-colitis, IL-10 knockout mice and TNBS colitis), but the effects occur at high doses ranging from 13 mg/Kg body weight17,18that may not necessarily be restricted to actions at A3AR. Furthermore, the anti-inflammatory mechanism of IB-MECA may be linked to a down-regulation of A3AR25. In a model of cardiac ischemia, A3AR knockout (A3/AR) is protective26, and not Talabostat mesylate all effects at A3AR are protective2729. Therefore, the role of A3AR in gut inflammation needs further clarification. Complex neural circuits in the ENS coordinate motility, secretion, vascular tone, epithelial transport and immune-responses in the gut to ensure effective digestion, absorption, transit of luminal contents, and elimination of waste products. Immune-neural communication is involved in response to pathogens, allergens in the diet, mucosal irritants, or gut inflammation, and host-defense mechanisms30. Experimental gut inflammation causes abnormalities in A1AR or A2AR leading to alterations in purinergic modulation Talabostat mesylate of enteric neurotransmission22,31. The role of A3AR in the ENS or other cells in.