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

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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.