Kumamoto University, Japan.
Biochem Pharmacol. 2010 Jun 1;79(11):1622-33. doi: 10.1016/j.bcp.2010.01.030. Epub 2010 Feb 2.
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.
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。我们之前曾提出，前列腺素 E2（PGE2）水平的降低和黏膜细胞凋亡都参与了 NSAID 引起的胃损伤的发展，这种凋亡是由细胞内 Ca2+浓度的增加以及内质网（ER）应激反应和线粒体功能障碍介导的。塞来昔布和瑞巴派特分别作为一种更安全的 NSAID 和抗溃疡药物在临床上使用。在这项研究中，我们研究了瑞巴派特对塞来昔布诱导的胃损伤的影响。在预先给予小剂量吲哚美辛的小鼠中，口服给予瑞巴派特可抑制塞来昔布诱导的黏膜细胞凋亡和损伤形成，但不会降低胃中的 PGE2 水平。瑞巴派特还抑制了塞来昔布诱导的细胞内 Ca2+浓度增加、内质网应激反应、线粒体功能障碍和细胞凋亡。我们还发现，瑞巴派特抑制电压依赖性 L 型 Ca2+通道激活剂诱导的细胞内 Ca2+浓度增加，而该通道的另一种阻断剂可抑制塞来昔布诱导的细胞内 Ca2+浓度增加。这些结果表明，塞来昔布激活电压依赖性 L 型 Ca2+通道，而瑞巴派特阻断这种激活，从而抑制塞来昔布诱导的细胞凋亡。我们认为瑞巴派特的这种新活性可能在保护胃黏膜免受塞来昔布诱导的损伤形成中发挥重要作用。
