Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis

Tomoaki Ishihara, Ken Ichiro Tanaka, Saki Tashiro, Kosuke Yoshida, Tohru Mizushima

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

A major clinical problem encountered with the use of non-steroidal anti-inflammatory drugs (NSAIDs) is gastrointestinal complications. We have previously suggested that both decreases in prostaglandin E2 (PGE2) levels and mucosal apoptosis are involved in the development of NSAID-produced gastric lesions and that this apoptosis is mediated by an increase in the intracellular Ca2+ concentration and the resulting endoplasmic reticulum (ER) stress response and mitochondrial dysfunction. Celecoxib and rebamipide are being used clinically as a safer NSAID and an anti-ulcer drug, respectively. In this study, we have examined the effect of rebamipide on celecoxib-induced production of gastric lesions. In mice pre-administered with a low dose of indomethacin, orally administered rebamipide suppressed celecoxib-induced mucosal apoptosis and lesion production but did not decrease in PGE2 levels in the stomach. Rebamipide also suppressed celecoxib-induced increases in intracellular Ca2+ concentration, the ER stress response, mitochondrial dysfunction and apoptosis in vitro. We also found that rebamipide suppresses the increases in intracellular Ca2+ concentration induced by an activator of voltage-dependent L-type Ca2+ channels and that another blocker of this channel suppresses celecoxib-induced increases in intracellular Ca2+ concentration. These results suggest that celecoxib activates voltage-dependent L-type Ca2+ channels and that rebamipide blocks this activation, resulting in suppression of celecoxib-induced apoptosis. We believe that this novel activity of rebamipide may play an important role in the protection of gastric mucosa against the formation of celecoxib-induced lesions.

Original languageEnglish
Pages (from-to)1622-1633
Number of pages12
JournalBiochemical Pharmacology
Volume79
Issue number11
DOIs
Publication statusPublished - 2010 Jun 1

Keywords

  • Apoptosis
  • Celecoxib
  • Rebamipide
  • Ulcer
  • Voltage-dependent L-type Ca channel

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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  • Cite this

    Ishihara, T., Tanaka, K. I., Tashiro, S., Yoshida, K., & Mizushima, T. (2010). Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis. Biochemical Pharmacology, 79(11), 1622-1633. https://doi.org/10.1016/j.bcp.2010.01.030