Arachidonic acid metabolites, prostaglandins and leukotrienes, have been implicated as important mediators of the inflammatory response after tissue injury. Although there is good evidence that certain classes of prostaglandins and leukotrienes are produced within the central nervous system (CNS), the contribution these factors make to neuropathic conditions remains uncertain. In order to uncover mechanisms that regulate cellular events during the early phase of CNS damage, our laboratory has developed methods to isolate and grow specific populations of CNS glia, to identify brain cells by a variety of immunohistochemical techniques, and to monitor in vivo a number of tissue responses to CNS injury. Our investigations of the damaged CNS mesh nicely with the biochemical expertise of Wu and collaborators. We Propose a joint study to examine some simple but fundamentally important issues regarding brain eicosanoids. Using highly enriched cultures of microglia, astroglia, and oligodendroglia as well as preparations of neurons, we will characterize arachidonic acid metabolism for specific classes of cells within the nervous system. We will test the ability of immunomodulators to stimulate the production of brain eicosanoids including prostaglandins and leukotrienes. We will also determine the effectiveness of a variety of drugs to inhibit brain eicosanoid metabolism in vitro. In vivo studies will complement the examination of brain cell cultures. We will measure arachidonic acid metabolites in regions of penetrating brain injury and at sites of spinal cord infarction. Based upon these studies, we will next determine the ability of prostaglandins and leukotrienes to open the blood brain barrier, and to induce tissue edema in rat cerebral cortex or rabbit spinal cord. We will also investigate the in vivo action of immunomodulators as well as a variety of inhibitory drugs upon brain arachidonic acid metabolism. If successful, this proposed research will establish the cellular sources of brain prostaglandins and leukotrienes, will determine the contribution of eicosanoids to brain inflammation, and will assess the benefits of drug therapies.
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