Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity.
Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity.
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DOI：
10.1016/j.bcp.2012.09.016
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发表时间：
2012-12
影响因子：
5.8
通讯作者：
Shintaro Suemasu;N. Yamakawa;T. Ishihara;Teita Asano;Kayoko Tahara;Ken-ichiro Tanaka;H. Matsui;Yoshinari Okamoto;M. Otsuka;K. Takeuchi;Hidekazu Suzuki;T. Mizushima
中科院分区：
文献类型：
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作者：
Shintaro Suemasu;N. Yamakawa;T. Ishihara;Teita Asano;Kayoko Tahara;Ken-ichiro Tanaka;H. Matsui;Yoshinari Okamoto;M. Otsuka;K. Takeuchi;Hidekazu Suzuki;T. Mizushima
我们先前提出，非甾体抗炎药的直接细胞毒性是由于它们的膜通透性，以及它们降低胃前列腺素E_2的能力，导致了胃损伤的产生。与洛索洛芬(LOX)相比，氟洛洛芬(F-LOX)具有更低的膜通透性和胃溃疡形成活性，但抗炎活性相似。在这项研究中，我们研究了这种低溃烂活性的机制。与LOX相比，给予F-LOX后胃粘膜细胞死亡水平较低。然而，两种非甾体抗炎药治疗后的胃液前列腺素E2水平相似。口服前给予F-LOX对随后给予LOX引起的胃损伤具有保护作用，口服F-LOX可增加胃的pH值和粘液含量。在胃酸分泌刺激剂存在的情况下，F-LOX和LOX的溃疡形成活性差异不明显。此外，在有F-LOX存在的培养的胃细胞中观察到粘液的增加，这种增加依赖于细胞内cAMP水平的增加。这些结果表明，F-LOX的低致溃疡活性与其低的直接细胞毒性和对胃病变的保护作用有关。这种保护作用似乎是通过增加保护因子(粘液)和减少侵略性因子(酸)来实现的。
We previously proposed that direct cytotoxicity of NSAIDs due to their membrane permeabilization activity, together with their ability to decrease gastric prostaglandin E2, contributes to production of gastric lesions. Compared to loxoprofen (LOX), fluoro-loxoprofen (F-LOX) has much lower membrane permeabilization and gastric ulcerogenic activities but similar anti-inflammatory activity. In this study, we examined the mechanism for this low ulcerogenic activity in rats. Compared to LOX, the level of gastric mucosal cell death was lower following administration of F-LOX. However, the gastric level of prostaglandin E2was similar in response to treatment with the two NSAIDs. Oral pre-administration of F-LOX conferred protection against the formation of gastric lesions produced by subsequent administration of LOX and orally administered F-LOX resulted in a higher gastric pH value and mucus content. In the presence of a stimulant of gastric acid secretion, the difference in the ulcerogenic activity of F-LOX and LOX was less apparent. Furthermore, an increase in the mucus was observed in gastric cells cultured in the presence of F-LOX in a manner dependent of increase in the cellular level of cAMP. These results suggest that low ulcerogenic activity of F-LOX involves its both low direct cytotoxicity and protective effect against the development of gastric lesions. This protective effect seems to be mediated through an increase in a protective factor (mucus) and a decrease in an aggressive factor (acid).