Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis
Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis
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DOI：
10.1016/j.bcp.2010.01.030
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发表时间：
2010-06-01
影响因子：
5.8
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
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作者：
Ishihara, Tomoaki;Tanaka, Ken-Ichiro;Mizushima, Tohru
使用非甾体抗炎药（NSAIDs）时遇到的一个主要临床问题是胃肠道并发症。我们之前已经提出，前列腺素E-2 （PGE(2)）水平的降低和粘膜凋亡都参与了nsaid产生的胃病变的发展，并且这种凋亡是由细胞内Ca2+浓度的增加和由此产生的内质网（ER）应激反应和线粒体功能障碍介导的。塞来昔布和利巴米胺分别作为更安全的非甾体抗炎药和抗溃疡药在临床上使用。在这项研究中，我们研究了利巴米胺对塞来昔布诱导的胃病变的影响。在预先给予低剂量吲哚美辛的小鼠中，口服利巴米胺抑制塞来昔布诱导的粘膜凋亡和病变产生，但没有降低胃中PGE(2)的水平。利巴米胺还抑制塞来昔布诱导的细胞内Ca2+浓度升高、内质网应激反应、线粒体功能障碍和细胞凋亡。我们还发现，利巴米胺抑制由电压依赖性l型Ca2+通道激活剂诱导的细胞内Ca2+浓度的增加，而该通道的另一种阻滞剂抑制塞来昔布诱导的细胞内Ca2+浓度的增加。这些结果表明，塞来昔布激活电压依赖性l型Ca2+通道，而利巴米胺阻断这种激活，导致塞来昔布诱导的细胞凋亡受到抑制。我们认为，利巴米胺的这种新活性可能在保护胃黏膜免受塞来昔布诱导病变的形成中发挥重要作用。(C) 2010爱思唯尔公司版权所有。
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 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 PGE(2) 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. (C) 2010 Elsevier Inc. All rights reserved.