The broad, long-term objective of this research proposal is to determine the mechanism of ischemic brain injury caused by platelet activating factor (PAF). The hypothesis states that PAF impairs recovery of cere- bral blood flow (CBF) and energy metabolism in ischemic brain by promot- ing the synthesis of vasoactive eicosanoids such as thromboxane A2 (TXA2) and leukotriene C4 (LTC4).
The specific aims are: 1) to compare levels of TXA2 metabolite and LTC4 in ischemic brain treated with a PAF receptor antagonist, a TX synthase inhibitor combined with a TXA2 receptor antagonist, or a 5-lipoxygenase inhibitor, 2) to determine the effect of PAF receptor antagonism on mRNA transcription and synthesis of cyclo-oxygenase, phospholipase, and c-fos-related protein, 3) to compare measurements of blood flow in ischemic brain treated with a PAF receptor antagonist, a TX synthase inhibitor combined with a TXA2 receptor antag- onist, or a 5-lipoxygenase inhibitor, 4) to determine the effect of PAF receptor antagonism on postischemic restoration of high-energy phosphate metabolism, and 5) to determine the effect of PAF receptor antagonism on histologic change associated with postischemic tissue injury. The health-related purpose- of this project is to foster development of new stroke therapies by improving understanding of biochemical abnormalities contributing to ischemic brain injury. The experimental design uses the four-vessel occlusion model of reversible forebrain ischemia to test the hypothesis and accomplish the specific aims. Experimental methodology will include enzyme immunoassay of PAF and eicosanoids, northern and western blot analyses, measurement of cortical perfusion changes and regional CBF, in vivo phosphorus-31 magnetic resonance spectroscopy, and computerized quantitation of histological injury.
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