Dopamine D2–Receptor Antagonists Ameliorate Indomethacin-Induced Small Intestinal Ulceration in Mice by Activating α7 Nicotinic Acetylcholine Receptors

Abstract

Abstract.We have reported that nicotine and the specific α7AChR agonist ameliorate indomethacin-induced intestinal lesions in mice by activating α7 nicotinic acetylcholine receptors (α7nAChR). Dopamine D 2 -receptor antagonists, such as domperidone and metoclopramide, enhance the release of ACh from vagal efferent nerves. The present study examined the effects of domperidone and metoclopramide on indomethacin-induced small intestinal ulceration in mice, focusing on the α7AChR. Male C57BL/6 mice were administered indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Domperidone (0.1 -10 mg/kg) and metoclopramide (0.03 -0.3 mg/kg) were administered i.p. twice, at 0.5 h before and 8 h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7nAChR, 30 mg/kg) was administered twice, at 0.5 h before each domperidone treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine, mostly to the jejunum and ileum, with a concomitant increase in myeloperoxidase (MPO) activity. Domperidone suppressed the severity of lesions and the increase in MPO activity at low doses (0.1 -3 mg/kg), but not at a high dose (10 mg/kg). Similar effects were also observed by metoclopramide. The protective effects of domperidone and metoclopramide were totally abolished by prior administration of methyllycaconitine. Indomethacin treatment markedly enhanced inducible nitric oxide synthase and chemokine mRNA expression in the small intestine, but these responses were all significantly attenuated by either domperidone or metoclopramide. These findings suggest that dopamine D 2 -receptor antagonists ameliorate indomethacin-induced small intestinal ulceration through the activation of endogenous anti-inflammatory pathways mediated by α7nAChR.

Effect of Mosapride on Prednisolone-Induced Gastric Mucosal Injury and Gastric-Emptying Disorder in Dog

“…Other conventional prokinetic agents have also been reported to have an anti-ulcerogenic action in rat gastric mucosal injury models. In a previous study, the dopamine D 2 receptor antagonists metoclopramide and domperidone ameliorated small intestinal ulcers through cholinergic receptor stimulation followed by dopamine D 2 receptor inhibition in an indomethacin ulcer model [32]. Further studies may be required to assess the anti-ulcerogenic action of conventional prokinetic agents such as metoclopramide in dogs In this study, gastric emptying was delayed by prednisolone administration.…”

Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy

“…For example, in a mouse model of acute indomethacin-induced intestinal damage, Yasuda et al [125] found that dopamine D2 receptor antagonists reduced the severity of damage, and these effects were mediated through the activation of endogenous anti-inflammatory pathways mediated by via a7-nicotinic acetylcholine receptors, as had been observed previously [126] . Using the same model, Kato et al [127] demonstrated that certain 5-HT receptors could modulate susceptibility to NSAID-enteropathy.…”

NOX1/NADPH Oxidase Expressed in Colonic Macrophages Contributes to the Pathogenesis of Colonic Inflammation in Trinitrobenzene Sulfonic Acid–Induced Murine Colitis

“…The homogenized samples were subjected to three freeze-thaw cycles and centrifuged at 500g for 10 minutes. MPO activity in the supernatant was determined spectrophotometrically at 450 nm using o-dianisidine hydrochloride (Sigma-Aldrich, St. Louis, MO), as described previously (Yasuda et al, 2011). Sample protein content was estimated using a bicinchoninic acid spectrophotometric assay kit (Pierce, Rockford, IL).…”

“…Excised colon tissues were rinsed with cold PBS, homogenized in ice-cold Krebs-HEPES buffer (pH 7.4) containing a cocktail of protease inhibitors (Complete Mini; Roche, Mannheim, Germany), and then centrifuged at 1100g at 4°C for 15 minutes. The production of ROS (primarily superoxide) was determined via a chemiluminescence assay using L-012 (Wako) as described previously (Yasuda et al, 2011).…”