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 polyamine products in the pathophysiology of cerebral ischemia. This proposal examines the regulation of ODC enzyme activity, which in turn regulates polyamine synthesis after transient cerebral ischemia. The events we hypothesize as regulating ODC enzyme activity include: 1) the involvement of the polyamine binding site at the N-methyl-D-aspartate (NMDA) receptor by a feed back mechanism 2) activation of the phospholipase C and phospholipase A2 pathways by altering ODC gene expression and thus ODC enzyme activity and 3) activation of protein kinase C by altering ODC gene expression and thus ODC enzyme activity after the onset of ischemia. 4) Interconversion of polyamines after they are formed by a feed back mechanism. Questions to be evaluated in the gerbil hippocampus after transient cerebral ischemia are how the ODC enzyme activity and gene expression are regulated by: 1) modulation of the NMDA receptor and polyamine binding site, 2) modulation of the phospholipase C and phospholipase A2 pathways, 3) modulation of protein kinase C, and 4) interaction of polyamine analogs at the NMDA-receptor polyamine binding site. Biochemical (enzyme activity, tissue polyamine quantification), molecular biology (mRNA quantification), and histopathological (neuronal counts) methods, and physiological measurements (edema formation by specific gravity methods) will be used to further assess the role of ODC enzyme activity and gene expression in the pathological events following transient cerebral ischemia. Completion of these studies will increase our understanding of the regulation of the harmful and beneficial metabolic events after transient cerebral ischemia which influence outcome.
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