权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基于活性氧产生抑制作用的新型抗炎药的开发

基本信息

批准号：
03557104
负责人：
ISHIBASHI Sadahiko
金额：
$ 3.2万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

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.

中性粒细胞产生活性氧，作为提供杀菌因子的重要功能，但由于这些活性氧的高反应性，有时会诱发炎症、癌症、衰老等。因此，生产应控制在适当的水平。所谓的NADPH氧化酶是细胞膜上的一种多组分酶，负责产生超氧阴离子O_2^-，这是活性氧的主要产物。从我们之前发现的一种含硒化合物Ebselen能显著抑制O_2^-的产生开始，我们研究了Ebselen对不同类型炎症实验模型的影响。撇开炎症不谈，偶然发现艾布selen对大鼠缺血性脑水肿非常有效，其中活性氧很可能参与其中。未发现严重不良反应。此后，人们开始进行临床研究，将该药用于治疗蛛网膜下腔出血和脑梗死。随着研究的进行，该药剂已被证明是显著有效的。由于我们之前也报道了几种与艾布selen相关的化合物可以有效抑制O_2^-的产生，因此研究人员正在继续研究它们的抗炎作用。有些药物的效果比艾布selen更强。这些类似物的作用主要从构效关系和硒在抑制O_2^-生成中的作用等方面进行研究。探讨了其作用机制，特别是对多种组织蛋白激酶C的抑制作用。此外，还对O_2^-的调控进行了基础研究。