Rebamipide, a gastro-protective drug, inhibits indomethacin-induced apoptosis in cultured rat gastric mucosal cells: association with the inhibition of growth arrest and DNA damage-induced 45 alpha expression.

Rebamipide, a gastromucosal protective drug, suppresses indomethacin-induced gastropathy in humans and rodents. Effects of rebamipide on gene expression in indomethacin-treated gastric mucosal cells (RGM1) were investigated using high-density oligonucleotide arrays. Indomethacin induced apoptosis in RGM1 cells in a dose-dependent manner. Rebamipide pretreatment significantly reduced indomethacin-induced apoptosis. We used gene expression profiling on high-density oligonucleotide probe arrays to characterize the transcriptional response of RGM1 cells to indomethacin treatment for 6 hr. Of the 8,799 probes examined, 717 (8.1%) were induced (400 probes) or repressed (317 probes) at least 1.5-fold. Among the 158 genes that were induced by indomethacin at least 2.0-fold, four genes that were down-regulated by rebamipide at least 2.0-fold are listed: growth arrest and DNA-damage-inducible 45 alpha (GADD 45 alpha), golgi SNAP receptor complex member 1, iodothyronine deiodinases, and transcription factor 8. Real time-PCR confirmed GADD 45 alpha expression and its inhibition by rebamipide. Inhibition of apoptosis-related genes is possibly important for the cytoprotective effect of rebamipide against indomethacin-induced gastric mucosal cell injury.