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 language | English |
|---|---|
| Pages (from-to) | 1622-1633 |
| Number of pages | 12 |
| Journal | Biochemical Pharmacology |
| Volume | 79 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2010 Jun |
| Externally published | Yes |
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Keywords
- Apoptosis
- Celecoxib
- Rebamipide
- Ulcer
- Voltage-dependent L-type Ca channel
ASJC Scopus subject areas
- Pharmacology
- Biochemistry
Cite this
Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis. / Ishihara, Tomoaki; Tanaka, Ken Ichiro; Tashiro, Saki; Yoshida, Kosuke; Mizushima, Tohru.
In: Biochemical Pharmacology, Vol. 79, No. 11, 06.2010, p. 1622-1633.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis
AU - Ishihara, Tomoaki
AU - Tanaka, Ken Ichiro
AU - Tashiro, Saki
AU - Yoshida, Kosuke
AU - Mizushima, Tohru
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Celecoxib
KW - Rebamipide
KW - Ulcer
KW - Voltage-dependent L-type Ca channel
UR - http://www.scopus.com/inward/record.url?scp=77950080219&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950080219&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2010.01.030
DO - 10.1016/j.bcp.2010.01.030
M3 - Article
VL - 79
SP - 1622
EP - 1633
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 11
ER -