Abstract

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.

  Funding Agency

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

  Institution

Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Tyurina, Yulia Y; Lou, Wenjia; Qu, Feng et al. (2017) Lipidomics Characterization of Biosynthetic and Remodeling Pathways of Cardiolipins in Genetically and Nutritionally Manipulated Yeast Cells. ACS Chem Biol 12:265-281
Schuck, Robert N; Zha, Weibin; Edin, Matthew L et al. (2014) The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease. PLoS One 9:e110162
Shaik, Jafar Sadik B; Ahmad, Muzamil; Li, Wenjin et al. (2013) Soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid is neuroprotective in rat model of ischemic stroke. Am J Physiol Heart Circ Physiol 305:H1605-13
Theken, Katherine N; Deng, Yangmei; Schuck, Robert N et al. (2012) Enalapril reverses high-fat diet-induced alterations in cytochrome P450-mediated eicosanoid metabolism. Am J Physiol Endocrinol Metab 302:E500-9
Theken, Katherine N; Deng, Yangmei; Kannon, M Alison et al. (2011) Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism. Drug Metab Dispos 39:22-9
Miller, Tricia M; Donnelly, Mark K; Crago, Elizabeth A et al. (2009) Rapid, simultaneous quantitation of mono and dioxygenated metabolites of arachidonic acid in human CSF and rat brain. J Chromatogr B Analyt Technol Biomed Life Sci 877:3991-4000
Li, Jiang; Wilson, Annette; Gao, Xiang et al. (2009) Coordinated regulation of dimethylarginine dimethylaminohydrolase-1 and cationic amino acid transporter-1 by farnesoid X receptor in mouse liver and kidney and its implication in the control of blood levels of asymmetric dimethylarginine. J Pharmacol Exp Ther 331:234-43
Mu, Ying; Klamerus, Megan M; Miller, Tricia M et al. (2008) Intravenous formulation of N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) for inhibition of rat brain 20-hydroxyeicosatetraenoic acid formation. Drug Metab Dispos 36:2324-30
Nayeem, Mohammed A; Poloyac, Samuel M; Falck, John R et al. (2008) Role of CYP epoxygenases in A2A AR-mediated relaxation using A2A AR-null and wild-type mice. Am J Physiol Heart Circ Physiol 295:H2068-78
Poloyac, Samuel M; Zhang, Yuqing; Bies, Robert R et al. (2006) Protective effect of the 20-HETE inhibitor HET0016 on brain damage after temporary focal ischemia. J Cereb Blood Flow Metab 26:1551-61