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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001505-05
Application #
2259379
Study Section
NST-2 Subcommittee (NST)
Project Start
1991-04-01
Project End
1996-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Neurology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Pettigrew, L C; Holtz, M L; Craddock, S D et al. (1996) Microtubular proteolysis in focal cerebral ischemia. J Cereb Blood Flow Metab 16:1189-202
Smith-Swintosky, V L; Pettigrew, L C; Sapolsky, R M et al. (1996) Metyrapone, an inhibitor of glucocorticoid production, reduces brain injury induced by focal and global ischemia and seizures. J Cereb Blood Flow Metab 16:585-98
Holtz, M L; Kindy, M S; Craddock, S et al. (1996) Induction of PGH synthase and c-fos mRNA during early reperfusion of ischemic rat brain. Brain Res Mol Brain Res 35:339-43
Pettigrew, L C; Meyer, J J; Craddock, S D et al. (1995) Delayed elevation of platelet activating factor in ischemic hippocampus. Brain Res 691:243-7
Ryan, S J; Pettigrew, L C (1995) Cranial arteriopathy in familial Vogt-Koyanagi-Harada syndrome. J Neuroimaging 5:244-5
Geddes, J W; Schwab, C; Craddock, S et al. (1994) Alterations in tau immunostaining in the rat hippocampus following transient cerebral ischemia. J Cereb Blood Flow Metab 14:554-64
Smith-Swintosky, V L; Pettigrew, L C; Craddock, S D et al. (1994) Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury. J Neurochem 63:781-4
Cai, W M; Hatton, J; Pettigrew, L C et al. (1994) A simplified high-performance liquid chromatographic method for direct determination of warfarin enantiomers and their protein binding in stroke patients. Ther Drug Monit 16:509-12
Pettigrew, L C; Kryscio, R J (1993) Thromboxane receptor antagonism and synthase inhibition in cerebral ischemia. Prostaglandins Leukot Essent Fatty Acids 48:211-7
Dean, B L; Lee, C; Kirsch, J E et al. (1992) Cerebral hemodynamics and cerebral blood volume: MR assessment using gadolinium contrast agents and T1-weighted Turbo-FLASH imaging. AJNR Am J Neuroradiol 13:39-48

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