Activation of α7 nicotinic acetylcholine receptors ameliorates indomethacin-induced small intestinal ulceration in mice

Cholinergic anti-inflammatory actions have been shown to result mainly from the activation of alpha 7 nicotinic acetylcholine receptors Here we investigated the possible role of alpha 7 nicotinic acetylcholine receptors in the pathogenesis of indomethacin-induced small intestinal ulceration in mice Male C57BL/6 mice were given indomethacin (10 mg/kg s c) and sacrificed 24 h later Nicotine 03-3 mg/kg) and PNU-282987 (a selective agonist of alpha 7 nicotinic acetylcholine receptors 1-10 mg/kg) wen administered i p twice at 05 h before and 8 h after indomethacin treatment while methyllycaconitine (a selective antagonist of alpha 7 nicotinic acetylcholine receptors 10 mg/kg was administered twice at 05 h before each nicotine treatment Indomethacin caused severe hemorrhagic lesions in the small intestine with marked increases in myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS) expression in the mucosa Pretreatment with nicotine reduced the seventy of intestinal lesions in a dose-dependent manner The protective effect of nicotine was mimicked by PNU-282987 and significantly attenuated by methyllycaconitine The increases in MPO activity and NOS expression induced by indomethacin were also significantly suppressed by nicotine and PNU-282987 Immunohistochemical study showed that the expression of alpha 7 nicotinic acetylcholine receptors was clearly enhanced in the submucosa of the damaged area following indomethacin treatment These results suggest that the activation of alpha 7 nicotinic acetylcholine receptors ameliorates indomethacin-induced small intestinal ulceration and that this effect may result from the inhibition of iNOS expression and neutrophil migration (C) 2010 Elsevier B V All rights reserved