Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis.
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 E(2) (PGE(2)) 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 Ca(2+) 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 PGE(2) levels in the stomach. Rebamipide also suppressed celecoxib-induced increases in intracellular Ca(2+) concentration, the ER stress response, mitochondrial dysfunction and apoptosis in vitro. We also found that rebamipide suppresses the increases in intracellular Ca(2+) concentration induced by an activator of voltage-dependent L-type Ca(2+) channels and that another blocker of this channel suppresses celecoxib-induced increases in intracellular Ca(2+) concentration. These results suggest that celecoxib activates voltage-dependent L-type Ca(2+) 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.
Kumamoto University, Japan.
Tomoaki
T
Ishihara
Ken-Ichiro
K
Tanaka
Saki
S
Tashiro
Kosuke
K
Yoshida
Tohru
T
Mizushima
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D000897:Anti-Ulcer Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D000068579:Celecoxib; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects; D005753:Gastric Mucosa / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020011:Protective Agents; D011720:Pyrazoles / Q000009:adverse effects*; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D015220:Calcium Channels; D052246:Cyclooxygenase 2 Inhibitors; D020011:Protective Agents; D011720:Pyrazoles; D015363:Quinolones; D013449:Sulfonamides; D000068579:Celecoxib; C052785:rebamipide; D000409:Alanine