2--3--dialdehyde-atp and 2-4-dinitrofluorobenzene-sulfonic-acid

Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Apoptosis Regulatory Proteins; Calcium; CARD Signaling Adaptor Proteins; Carrier Proteins; Caspases; Cell Death; Colitis; Connexins; Cytoskeletal Proteins; Dinitrofluorobenzene; Disease Models, Animal; Dose-Response Relationship, Drug; Estrenes; Gastrointestinal Motility; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myenteric Plexus; Nerve Tissue Proteins; Neurons; Nitric Oxide Synthase Type I; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphodiesterase Inhibitors; Purinergic P2X Receptor Agonists; Pyrrolidinones; Receptors, Purinergic P2X7; Signal Transduction; Time Factors