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Digestive Diseases and Sciences

, Volume 50, Supplement 1, pp S76–S83 | Cite as

Rebamipide Significantly Inhibits Indomethacin-Induced Mitochondrial Damage, Lipid Peroxidation, and Apoptosis in Gastric Epithelial RGM-1 Cells

  • Yumiko Nagano
  • Hirofumi Matsui
  • Mutsumi Muramatsu
  • Osamu Shimokawa
  • Takeshi Shibahara
  • Akinori Yanaka
  • Akira Nakahara
  • Yasushi Matsuzaki
  • Naomi Tanaka
  • Yukio Nakamura
Article

Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs) cause complications such as gastrointestinal injury. NSAIDs were recently reported to cause mitochondrial injury: to dissipate the mitochondrial transmembrane potential (MTP), and to induce mitochondrial permeability transition pore (PTP), which liberates cytochrome c. This enzyme generates reactive oxygen species (ROS) thereby triggers caspase cascade and cellular lipid peroxidation, resulting in cellular apoptosis. However, the mechanism of this NSAID-induced MTP's role in cellular apoptosis remains unknown. Rebamipide, an antiulcer drug, is reported to scavenge ROS and to show the protective effects on indomethacin-induced tissue peroxidations. Since cytochrome c and its generation of ROS are involved in indomethacin-induced cellular apoptosis, rebamipide may attenuate mitochondrial damage. The aim of this study was to elucidate whether indomethacin induces both the MTP decrease and cellular apoptosis, and the effect of rebamipide on these phenomena. We examined the effect of rebamipide on 1) MTP change, 2) lipid peroxidation, 3) apoptosis, and 4) caspase activation using gastric mucosal epithelial cell-line treated with indomethacin. With a specially designed fluorescence analyzing microscope system, MTP change, cellular lipid peroxidation, and cellular apoptosis were investigated with the ⋆ following fluorescent dyes, MitoRed, DPPP, and Hoechst 33258, respectively. Indomethacin treatment decreased MTP but increased both cellular lipid peroxidation and cellular apoptosis via caspase 3 and 9 activation. Rebamipide clearly inhibited these phenomena {in vitro}. We demonstrated that fluorescent dyes such as MitoRed, DPPP, and Hoechst 33258 are useful indicators for detecting oxidative cellular injuries in living cells. Rebamipide exerts a protective effect on mitochondrial membrane stability in gastric epithelial cells.

Key Words

NSAIDs apoptosis mitochondria ROS (reactive oxygen species) fluorescence 

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Yumiko Nagano
    • 1
    • 2
  • Hirofumi Matsui
    • 1
    • 2
  • Mutsumi Muramatsu
    • 1
  • Osamu Shimokawa
    • 1
    • 2
  • Takeshi Shibahara
    • 1
  • Akinori Yanaka
    • 1
  • Akira Nakahara
    • 1
  • Yasushi Matsuzaki
    • 1
  • Naomi Tanaka
    • 1
  • Yukio Nakamura
    • 2
  1. 1.Division of Gastroenterology, Graduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
  2. 2.Cell Engineering DivisionBio Resource Center, RIKENTsukubaJapan

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