Effect of Rebamipide on Acetic Acid-induced Gastric Ulcer in Rats: Involvement of Hepatocyte Growth Factor

Udagawa, Akihide; Shiota, Goshi; Ichiba, Miho; Murawaki, Yoshikazu

doi:10.1080/00365520310000609

Cited by 20 publications

(14 citation statements)

References 33 publications

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“…It accelerates gastric ulcer healing and reduces the rate of ulcer recurrence (24,26). These protective effects of rebamipide are thought to be mediated by the production of prostaglandin after the induction of cyclooxygenase, the induction of growth factors such as hepatocyte growth factor, vascular endothelial growth factor, and fibroblast growth factor, and its anti-oxidant properties, which involve the scavenging of hydroxyl radicals and the suppression of superoxide production by activated neutrophils (25,34,42,43). In addition, the present experiments showed that rebamipide administration reduced the levels of LPO, nitrotyrosine, and the tyrosine nitration of ERK in PHT gastric mucosa to normal.…”

Section: Discussionmentioning

confidence: 99%

Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

Kinjo¹,

Kawanaka²,

Akahoshi³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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tal hypertensive (PHT) gastric mucosa increases susceptibility to injury and delayed mucosal healing. It is possible that nitration of ERK by peroxynitrite might alter MAPK (ERK) signaling in PHT gastric mucosa, leading to delayed mucosal healing, since excessive nitric oxide production is implicated in PHT gastric mucosa and MAPK (ERK) signaling induces cell proliferation and leads to gastric mucosal healing in response to injury. Portal hypertension was produced by staged portal vein ligation, and sham-operation (SO) rats served as controls. Lipid peroxide (LPO) and nitrotyrosine increased significantly in PHT gastric mucosa compared with SO rats. ERK activation was impaired in PHT gastric mucosa in response to ethanol injury, whereas no significant difference in the phosphorylation of MEK, an upstream molecule of ERK, was seen between the two groups. The nitration of ERK by peroxynitrite, as detected by the coimmunoprecipitation of ERK and nitrotyrosine, was significantly enhanced in PHT gastric mucosa. Administration of rebamipide, a gastroprotective drug that acts as an oxygen-derived free radical scavenger, significantly decreased LPO and nitrotyrosine as well as the nitration of ERK by peroxynitrite in PHT gastric mucosa, therefore normalizing ERK activation and restoring the gastric mucosal healing response to ethanol injury. Enhanced nitration of ERK by peroxynitrite is involved in the impaired MAPK (ERK) signaling in PHT gastric mucosa. These findings demonstrate a new molecular mechanism in which PHT gastric mucosa is predisposed to injury and impaired healing.

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Section: Discussionmentioning

confidence: 99%

Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

Kinjo¹,

Kawanaka²,

Akahoshi³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Such results suggest that the mechanism of healing in the liver is completely different from that of gastric ulcer healing. Based upon detailed examination in rats, Udagawa et al 119) suggested that the anti-ulcer effect of rebamipide involves upregulation of HGF, c-met, COX-2, and EP2 in the ulcer area. Brzozowski et al 120) examined the effects of HGF and gastrin on acetic acid ulcer healing in rats by local injection of specific antibodies against HGF and gastrin just around the ulcer immediately after ulcer induction.…”

Section: Growth Factors Epidermal Growth Factor (Egf)mentioning

confidence: 99%

An Overview of Acetic Acid Ulcer Models<br>—The History and State of the Art of Peptic Ulcer Research—

Okabe

Amagase

2005

Biological & Pharmaceutical Bulletin

208

166

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Four types of experimental chronic ulcer models, named acetic acid ulcer models, have been developed to examine the healing process of peptic ulcers, screen anti-ulcer drugs, and better evaluate the adverse effects of various anti-inflammatory drugs on the gastrointestinal mucosa. The model easily and reliably produces round, deep ulcers in the stomach and duodenum, allowing acetic acid ulcer production in mice, rats, Mongolian gerbils, guinea pigs, cats, dogs, miniature pigs, and monkeys. These ulcer models highly resemble human ulcers in terms of both pathological features and healing process. The models have been established over the past 35 years and are now used throughout the world by basic and clinical scientists. One of the characteristic features of acetic acid ulcers in rats is the spontaneous relapse of healed ulcers Ͼ100 d after ulceration, an endoscopically confirmed phenomenon. Indomethacin significantly delays the healing of acetic acid ulcers, probably by reducing endogenous prostaglandins and inhibiting angiogenesis in ulcerated tissue. Helicobacter pylori significantly delays healing of acetic acid ulcers and causes relapse of healed ulcers at a high incidence in Mongolian gerbils. Anti-secretory drugs (e.g. omeprazole), prostaglandin analogs, mucosal defense agents (e.g. sucralfate), and various growth factors all significantly enhance healing of acetic acid ulcers. Gene therapy with epidermal growth factor and vascular endothelial growth factor applied to the base of acetic acid ulcers in rats is effective in enhancing ulcer healing. Since an inhibitor of nitric oxide syntase prevents ulcer healing, nitric oxide might be involved in the mechanism underlying ulcer healing. We conclude that acetic acid ulcer models are quite useful for various studies related to peptic ulcers.

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“…The mechanisms of anti-ulcer and cytoprotective actions of rebamipide are mainly divided into the following 3 types: 1) acceleration of ulcer healing based on the induction of prostaglandin synthesis via COX-2 expression (30 -32) and its receptor (33) and up-regulation of growth factor and its receptors such as epidermal growth factor (EGF) (34), vascular endothelial growth factor (VEGF) (35), and hepatocyte growth factor (HGF) (36); 2) cytoprotective activities such as induction of mucus secretion (37); 3) anti-inflammatory activities such as free-radical scavenging effect (38 -40), inhibition of neutrophil activation, and migration (41,42) and inhibition of cytokines production from leukocytes (43).…”

Section: Introductionmentioning

confidence: 99%

Prophylactic Effect of Rebamipide on Aspirin-Induced Gastric Lesions and Disruption of Tight Junctional Protein Zonula Occludens-1 Distribution

et al. 2008

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Abstract. Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and antiinflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects.

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Effect of Rebamipide on Acetic Acid-induced Gastric Ulcer in Rats: Involvement of Hepatocyte Growth Factor

Abstract: sICAM-1 seems to be a poor diagnostic tool, but since plasma sICAM-1 concentrations decreased during the treatment period, it might prove to be applicable as an activity marker in the individual patient.

Cited by 20 publications

References 33 publications

Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

An Overview of Acetic Acid Ulcer Models<br>—The History and State of the Art of Peptic Ulcer Research—

Prophylactic Effect of Rebamipide on Aspirin-Induced Gastric Lesions and Disruption of Tight Junctional Protein Zonula Occludens-1 Distribution

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Effect of Rebamipide on Acetic Acid-induced Gastric Ulcer in Rats: Involvement of Hepatocyte Growth Factor

Abstract: sICAM-1 seems to be a poor diagnostic tool, but since plasma sICAM-1 concentrations decreased during the treatment period, it might prove to be applicable as an activity marker in the individual patient.

Cited by 20 publications

References 33 publications

Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

Significance of ERK nitration in portal hypertensive gastropathy and its therapeutic implications

An Overview of Acetic Acid Ulcer Models<br>&mdash;The History and State of the Art of Peptic Ulcer Research&mdash;

Prophylactic Effect of Rebamipide on Aspirin-Induced Gastric Lesions and Disruption of Tight Junctional Protein Zonula Occludens-1 Distribution

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An Overview of Acetic Acid Ulcer Models<br>—The History and State of the Art of Peptic Ulcer Research—