Development of anti-inflammatory agents of new type on the basis of the inhibitory effect on active oxygen production

中性粒细胞产生活性氧源，作为提供杀菌因子的重要功能，但这些活性氧源有时会导致炎症、癌症、衰老等，因为它们具有高反应性。因此，生产应该在适当的水平上进行调节。所谓的NADPH氧化酶是细胞膜中的一种多组分酶，负责产生超氧阴离子O_2^-，它是活性氧中的主要产物。从我们以前发现的一种含硒化合物ebselen显著抑制O_2~-产生开始，我们考察了ebselen对各种类型的实验性炎症模型的影响。除炎症外，还偶然发现依布硒对大鼠缺血性脑水肿的影响很大，其中很可能有活性氧的参与。未发现该制剂的严重不良反应。从那时起，临床研究一直在使用这种药物治疗蛛网膜下腔出血和脑梗塞。随着研究的深入，该制剂已被证明是有效的。由于我们之前也报道了几种与依布硒有关的化合物具有抑制O_2~-产生的作用，因此对其抗炎作用的研究正在进行中。其中一些显示出比依布司林更有效的作用。这些类似物的作用涉及构效关系和Selen在O_2产生抑制作用中的作用。探讨了它们的作用机制，特别是对不同组织中蛋白激酶C的抑制作用。此外，还对O_2~-产生的调节进行了基础研究。

Production of active oxygens by neutrophils, is important as a function to provide bactericidal factors, but these active oxygens cometimes induce inflammation, cancer, aging, etc., because of their high reactivity. Thus, the production should be regulated at the adequate level. So-called NADPH oxidase, a multi-component enzyme in cell membranes, a is responsible for the production of superoxide anion, O_2^-, a primary product among the active oxygens. Starting from our previous finding that Ebselen, a selen-containing compound, markedly suppresses O_2^- prodution, we examined the effect of Ebselen on various types of experimental model of inflammation. Slightly apart from inflammation, it was incidentally found that Ebselen was very efectice to ischemic brain edema in rats, in which the involvement of active oxygens was highly likely. No serious adverse reactions were detected for the agent. Since then, clinical researches have been undertaken to use this agent in the treatment of subarachnoid hemorrhage and brain infarction. As the researches have proceeded so far, the agent has proved to be markedly effective.Since we also reported earlier that several compounds related to Ebselen was effective in suppressing, O_2^- production, researches are proceeding to investigate their anti-inflammatory effect. Some showed more potent effect than Ebselen. The effects of these analogs were interested in aspects of structure-activity relationship and role of selen in O_2^- prodution-suppressing action. Mechanism for their effects were examined with special reference to the inhibitory effect on protein kinase C in various tissues.In addition, basic studies were made on regulation of O_2^- prodution.