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

Yasuda, Masashi; Kawahara, Ryoji; Hashimura, Hiroshi; Yamanaka, Naoaki; Iimori, Maho; Amagase, Kikuko; Kato, Shinichi; Takeuchi, Koji

doi:10.1254/jphs.11037fp

Cited by 22 publications

(20 citation statements)

References 44 publications

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“…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.…”

Section: Discussionmentioning

confidence: 63%

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

Tsukamoto

Ohno

Maeda

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. Previous report demonstrated that prokinetic agent mosapride has anti-ulcerogenic action in rat-indomethacin gastric mucosal injury model. Here, we assessed the prophylactic effect of mosapride on gastric mucosal injury and emptying disorder induced by prednisolone in dogs. Crossover study design was employed. Six healthy beagles were administered prednisolone alone (2 mg/kg, twice a day [BID] subcutaneously) and prednisolone with mosapride (1 mg/kg, BID, orally), followed by an interval of at least 6 weeks. In each treatment, gastric mucosal injury was scored endoscopically according to the modified Lanza scale, and gastric emptying was assessed with 13 C-octanoic acid breath test. The incidence of gastrointestinal adverse events was also investigated. Coadministration of mosapride with prednisolone significantly (P<0.05) reduced the gastric mucosal injury score (mean ± SD, 17.67 ± 6.96), compared with that of prednisolone treatment alone (25.50 ± 13.03). Prednisolone treatment delayed the half-emptying time (184 ± 45 min) compared with that of controls (137 ± 19 min), and coadministration of mosapride improved this gastric-emptying delay (143 ± 29 min). Furthermore, the incidence of the gastrointestinal adverse event vomiting became less frequent upon coadministration with mosapride. In addition to its prokinetic action, our study suggests that mosapride has an anti-ulcerogenic action in dogs. The use of mosapride in combination with prednisolone is effective for attenuating prednisolone-induced gastrointestinal adverse events. The corticosteroid prednisolone has been widely used for treating immune-mediated diseases such as immune-mediated hemolytic anemia, idiopathic polyarthritis, and atopic dermatitis [2,18,19]. However, this drug may cause gastric mucosal injury when administered at high doses [22]. Moreover, a previous study indicated that prednisolone can alter gastrointestinal motility [21,22] Mosapride, a selective 5-hydroxytryptamine-4 receptor (5-HT 4 R) agonist, promotes the release of acetylcholine in enteric nerves by activating 5-HT 4 R and thereby enhancing gastrointestinal motility [5,17]. Since cisapride was withdrawn from the market for its cardiac arrhythmia side effect, mosapride has been used as a prokinetic agent for the treatment of dyspeptic symptoms of gastrointestinal disorders such as chronic gastritis, functional dyspepsia, irritable bowel syndrome, and gastric esophageal reflux disease [5,17]. Mosapride also enhances upper gastrointestinal motility in dogs [29,33] and has been approved as a prokinetic agent for canines in Japan. We have previously demonstrated that mosapride is effective for treating vincristine-induced gastric motility disorder in dogs [28].In addition to its prokinetic action, recent findings suggest that mosapride mediates novel actions through 5-HT 4 R. Fujisawa et al. [7] demonstrated that mosapride attenuated gastric mucosal damage in a rat indomethacin gastric mucosal injury model. They demonstrated that this anti-ulcerogenic action of mosapride ...

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Section: Discussionmentioning

confidence: 63%

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

Tsukamoto

Ohno

Maeda

et al. 2012

The Journal of Veterinary Medical Science

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“…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.…”

Section: Nsaid-enteropathymentioning

confidence: 56%

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

Wallace¹

2013

WJG

151

148

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This article reviews the latest developments in understanding the pathogenesis, detection and treatment of small intestinal damage and bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs). With improvements in the detection of NSAID-induced damage in the small intestine, it is now clear that this injury and the associated bleeding occurs more frequently than that occurring in the stomach and duodenum, and can also be regarded as more dangerous. However, there are no proven-effective therapies for NSAIDenteropathy, and detection remains a challenge, particularly because of the poor correlation between tissue injury and symptoms. Moreover, recent studies suggest that commonly used drugs for protecting the upper gastrointestinal tract (i.e. , proton pump inhibitors) can significantly worsen NSAID-induced damage in the small intestine. The pathogenesis of NSAIDenteropathy is complex, but studies in animal models are shedding light on the key factors that contribute to ulceration and bleeding, and are providing clues to the development of effective therapies and prevention strategies. Novel NSAIDs that do not cause small in- FRONTIER

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“…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).…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

Section: Methodsmentioning

confidence: 99%

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

Yokota

Tsuzuki

Shimada

et al. 2016

J Pharmacol Exp Ther

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NOX1/NADPH oxidase, a nonphagocytic isoform of reactive oxygen species-producing enzymes, is highly expressed in the colon, but the physiologic and pathophysiologic roles of this isoform are not fully understood. The present study investigated the role of NOX1 in the development of colonic inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. Intrarectal injection of TNBS caused severe colitis accompanied by body weight loss, diarrhea, and increased myeloperoxidase (MPO) activity in wild-type (WT) mice. In contrast, the severity of colitis was significantly attenuated in NOX1-deficient (NOX1KO) mice (the inhibitions of macroscopic damage score, body weight loss, diarrhea score, and MPO activity were 73.1%, 36.8%, 83.3%, and 98.4%, respectively). TNBS-induced upregulation of inflammatory cytokines (tumor necrosis factor (TNF)-a and interleukin (IL)-1b), chemokines (CXCL1 and CXLC2), and inducible nitric oxide synthase (iNOS) was also significantly less in NOX1KO than in WT mice (the inhibitions were 100.8%, 89.0%, 63.5%, 96.7%, and 97.1%, respectively). Expression of NOX1 mRNA was detected not only in the lamina propria but also in peritoneal macrophages isolated from WT mice. Increased expression of TNF-a, IL-1b, and iNOS in peritoneal macrophages exposed to lipopolysaccharide was significantly attenuated in macrophages isolated from NOX1KO mice (68.1%, 67.0%, and 79.3% inhibition, respectively). These findings suggest that NOX1/NADPH oxidase plays an important role in the pathogenesis of TNBS-induced colonic inflammation via upregulation of inflammatory cytokines, chemokines, and iNOS. NOX1 in colonic macrophages may become a potential target in pharmacologic intervention for inflammatory bowel disease.

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

Cited by 22 publications

References 44 publications

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

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

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

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

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