Effect of 20-HETE inhibition on infarct volume and cerebral blood flow after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 2009 Mar;29(3):629-39
Date
12/25/2008Pubmed ID
19107134Pubmed Central ID
PMC2821901DOI
10.1038/jcbfm.2008.156Scopus ID
2-s2.0-61349178515 (requires institutional sign-in at Scopus site) 89 CitationsAbstract
This study examined the effects of an inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis, N-(3-chloro-4-morpholin-4-yl)phenyl-N'-hydroxyimido formamide (TS-011), on infarct volume, volume at risk, cerebral blood flow (CBF), and levels of cytochrome P450 (CYP450) eicosanoids in the brain after transient occlusion of the middle cerebral artery (t-MCAO) in rats. TS-011 (0.1 mg/kg, iv) reduced cortical infarct volume by approximately 70% and total infarct volume by 55%. TS-011 had no effect on the volume at risk or CBF during or up to 30 mins after the ischemic period. TS-011 reduced the delayed fall in CBF seen 2 h after reperfusion. The levels of CYP450 eicosanoids were similar in the ischemic and contralateral hemispheres after t-MCAO. TS-011 reduced 20-HETE levels in cerebral tissue by 80% but had no effect on the levels of EETs. Administration of another 20-HETE inhibitor, HET0016 (0.01 to 1.0 mg/kg, iv) or a 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (10 mg/kg, iv) also reduced infarct size. These results indicate that inhibitors of the synthesis or vasoconstrictor effects of 20-HETE reduce infarct size in rats after cerebral ischemia. The effects of TS-011 are not associated with changes in the area at risk or CBF and may be because of a potential protective effect in neurons subjected to ischemic stress.
Author List
Renic M, Klaus JA, Omura T, Kawashima N, Onishi M, Miyata N, Koehler RC, Harder DR, Roman RJAuthor
David Harder PhD, MS Emeritus Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBrain
Cerebrovascular Circulation
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme System
Disease Models, Animal
Formamides
Hydroxyeicosatetraenoic Acids
Infarction, Middle Cerebral Artery
Laser-Doppler Flowmetry
Male
Mass Spectrometry
Morpholines
Neuroprotective Agents
Rats
Rats, Wistar
