The long-range objective of this competing continuation research project is improved therapy for incomplete cerebral ischemia based on a better understanding of the role of ornithine decarboxylase (ODC) and its polyantines products in the pathophysiology of cerebral ischemia. Polyamines have both harmful and beneficial possible effects after ischemia. This balance of effects is dependent on ODC, the rate limiting enzyme of polyamine metabolism, and s-adenosyl methionine decarboxylase (SAMDC), an enzyme important in the synthesis of polyamines as well as in the relative distribution of the three major polyamines. Questions to be evaluated in the focal ischemia model include: 1) If changes in SAMDC activity contribute to disturbances in polyamine levels, 2) If administration of s-adenosyl methionine results in improvement in physiologic outcome, 3) If extracellular release of polyamines contribute to ischemic damage through the n-methyl-d-aspartate (NMDA) receptor, and 4) If combined blockade of extra and intracellular polyamines provides improvement. Questions to be evaluated in the transient ischemia model include: 1) If changes in SAMDC gene expression correlate with changes in enzyme and polyamine activity, 2) If metabolic recovery of high energy phosphates is a prerequisite for the enzyme system changes, 3) If polyamines have extracellular activity at NMDA receptors, and 4) If combined extra and intracellular blockade of polyamines decreases calcium dependent formation of other metabolites. MR spectroscopy, brain microdialysis, enzyme activity, molecular biological probes and electron microscopy will be used to assess ODC and SAMDC's role in the pathophysiologic events following cerebral ischemia. Completion of these studies will increase our understanding of the potentially harmful and beneficial metabolic events after incomplete cerebral ischemia leading to improved therapies to limit infarction.
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