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Rebamipide attenuates nonsteroidal anti-inflammatory drugs (NSAID) induced lipid peroxidation by the manganese superoxide dismutase (MnSOD) overexpression in gastrointestinal epithelial cells.
MedLine Citation:
PMID:  22653900     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Nonsteroidal anti-inflammatory drugs (NSAIDs) often cause gastrointestinal complications such as gastric ulcers and erosions. Recent studies on the pathogenesis have revealed that NSAIDs induce lipid peroxidation in gastric epithelial cells by generating superoxide anion in mitochondria, independently with cyclooxygenase-inhibition and the subsequent prostaglandin deficiency. Although not clearly elucidated, the impairment of mitochondrial oxidative phosphorylation, or uncoupling, by NSAIDs is associated with the generation of superoxide anion. Physiologically, superoxide is immediately transformed into hydrogen peroxide and diatomic oxygen with manganese superoxide dismutase (MnSOD). Rebamipide is an antiulcer agent that showed protective effects against NSAID-induced lipid peroxidation in gastrointestinal tracts. We hypothesized that rebamipide may attenuate lipid peroxidation by increasing the expression of MnSOD protein in mitochondria and decreasing the leakage of superoxide anion in NSAID-treated gastric and small intestinal epithelial cells. Firstly, to examine rebamipide increases the expression of MnSOD proteins in mitochondria of gastrointestinal epithelial cells, we underwent Western blotting analysis against anti-MnSOD antibody in gastric RGM1 cells and small intestinal IEC6 cells. Secondly, to examine whether the pretreatment of rebamipide decreases NSAID-induced mitochondrial impairment and lipid peroxidation, we treated these cells with NSAIDs with or without rebamipide pretreatment, and examined with specific fluorescent indicators. Finally, to examine whether pretreatment of rebamipide attenuates NSAID-induced superoxide anion leakage from mitochondria, we examined the mitochondria from indomethacin-treated RGM1 cells with electron spin resonance (ESR) spectroscopy using a specific spin-trapping reagent, CYPMPO. Rebamipide increased the expression of MnSOD protein, and attenuated NSAID-induced mitochondrial impairment and lipid peroxidation in RGM1 and IEC6 cells. The pretreatment of rebamipide significantly decreased the signal intensity of superoxide anion from the mitochondria. We conclude that rebamipide attenuates lipid peroxidation by increasing the expression of MnSOD protein and decreasing superoxide anion leakage from mitochondria in both gastric and small intestinal epithelial cells.
Authors:
Y Nagano; H Matsui; O Shimokawa; A Hirayama; M Tamura; Y Nakamura; T Kaneko; K Rai; H P Indo; H J Majima; I Hyodo
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of physiology and pharmacology : an official journal of the Polish Physiological Society     Volume:  63     ISSN:  1899-1505     ISO Abbreviation:  J. Physiol. Pharmacol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-06-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9114501     Medline TA:  J Physiol Pharmacol     Country:  Poland    
Other Details:
Languages:  eng     Pagination:  137-42     Citation Subset:  IM    
Affiliation:
The Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. hmatsui@md.tsukuba.ac.jp.
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