Decreasing tissue infarction in the ischemic penumbra is the primary therapeutic target after stroke. The degree of tissue damage in the ischemic penumbra is a function of the severity of the ischemic insult, which is a function of cerebral microvascular resistance. Recent studies have shown that the monohydroxylated metabolite of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE), is an important regulator of cerebrovascular resistance and mediates the vascular effects of nitric oxide. Our laboratory has recently shown that inhibiting 20-HETE formation dramatically reduces lesion volume after temporary focal ischemia. Based on this data, we hypothesize that 20-HETE is an important contributor to ischemic damage via its vasoconstrictive effects on the cerebral microvasculature. The goals of this project are: 1) To determine the temporal relationship between 20-HETE formation, lesion volume, and outcome in the rat temporary focal ischemia model; 2) To identify the in vivo effect of 20-HETE alterations on cerebral blood flow after temporary focal ischemia; 3) To determine the role of 20-HETE on nitric oxide mediated protective effects after temporary focal ischemia. This project will utilize combinations of in vivo blood flow assessment, molecular biology, and analytical chemistry techniques in the rat and transgenic mouse models of temporary focal ischemia. The results of this research are necessary to determine: 1) The role of 20-HETE in the pathogenesis of stroke; 2) The effects of 20-HETE on cerebrovascular regulation during ischemia and during post-ischemic hypoperfusion after stroke; 3) The role of 20-HETE inhibition in mediating the neuroprotective effects of nitric oxide. Elucidation of these mechanisms will enable future studies to delineate the therapeutic utility of 20-HETE inhibitors as a mechanism to reduce tissue damage after stroke. Furthermore, these studies will provide important information about the role of monohydroxylated arachidonic acid metabolites as a contributing pathway in the pathogenesis of stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052315-04
Application #
7414556
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (90))
Program Officer
Golanov, Eugene V
Project Start
2005-06-15
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$285,691
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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