The long-range objective of this application is to improve therapy for incomplete cerebral ischemia based on a better understanding of the pathophysiological role of ornithine decarboxylase in ischemic edema development. Ornithine decarboxylase (ODC), the ratelimiting enzyme for polyamine metabolism, is increased in brain regions developing ischlmic edema following both permanent focal and transient cerebral ischemia. Immunohistochemistry studies localized this increased ODC activity to neuronal cell bodies. Blockade of this enzyme prior to ischemia prevents blood brain barrier (BBB) breakdown following permanent focal ischemia. Models of permanent focal cerebral ischemia in the cat and transient cerebral ischemia in the gerbil will be used to assess the role of ODC in generating the different patterns of ischemic edema development produced by these two distinct ischemic insults. Questions to be evaluated in the focal ischemia model include: whether or not polyamines mediate ODC's effect on BBB breakdown, if maintenance of BBB integrity by ODC blockade improves edema development, if reduced edema development produced by ODC blockade improves physiologic outcome after ischemia and if ODC blockade started after the onset of ischemia still reduces cerebral edema and infarction development. Questions to be evaluated in the transient ischemia model include: whether or not increased ODC activity is responsible for BBB breakdown and cerebral edema development, if metabolic recovery is a prerequisite for increased ODC activity and if ODCmediated increases in BBB permeability results from increased endothelial cell membrane vesicular transport. Evans blue extravasation, intracranial pressure, specific gravity and total brain water will be used to assess ODC's role in BBB breakdown and ischemic edema development. Alterations in pathophysiological events produced by ODC blockade will be evaluated by measuring infarction volume, regional cerebral blood flow (hydrogen clearance), and metabolic state (nuclear magnetic resonance spectroscopy). Completion of these studies would greatly extend the understanding of ODC and its effects following cerebral ischemia and would serve as a basis for the possible use of ODC blockade in clinical studies.
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