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Protective effect of 20-HETE inhibition in a model of oxygen-glucose deprivation in hippocampal slice cultures. Am J Physiol Heart Circ Physiol 2012 Mar 15;302(6):H1285-93

Date

01/17/2012

Pubmed ID

22245774

Pubmed Central ID

PMC3311475

DOI

10.1152/ajpheart.00340.2011

Scopus ID

2-s2.0-84863229646   27 Citations

Abstract

Recent studies have indicated that inhibitors of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) may have direct neuroprotective actions since they reduce infarct volume after ischemia reperfusion in the brain without altering blood flow. To explore this possibility, the present study used organotypic hippocampal slice cultures subjected to oxygen-glucose deprivation (OGD) and reoxygenation to examine whether 20-HETE is released by organotypic hippocampal slices after OGD and whether it contributes to neuronal death through the generation of ROS and activation of caspase-3. The production of 20-HETE increased twofold after OGD and reoxygenation. Blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenol)formamidine (HET0016) or its actions with a 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, reduced cell death, as measured by the release of lactate dehydrogenase and propidium iodide uptake. Administration of a 20-HETE mimetic, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE), had the opposite effect and increased injury after OGD. The death of neurons after OGD was associated with an increase in the production of ROS and activation of caspase-3. These effects were attenuated by HET0016 and potentiated after the administration of 5,14-20-HEDE. These findings indicate that the production of 20-HETE by hippocampal slices is increased after OGD and that inhibitors of the synthesis or actions of 20-HETE protect neurons from ischemic cell death. The protective effect of 20-HETE inhibitors is associated with a decrease in superoxide production and activation of caspase-3.

Author List

Renic M, Kumar SN, Gebremedhin D, Florence MA, Gerges NZ, Falck JR, Harder DR, Roman RJ

Authors

Nashaat Gerges PhD Chair, Associate Professor in the School of Pharmacy Administration department at Medical College of Wisconsin
Suresh Kumar PhD Associate Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amidines
Animals
Animals, Newborn
Caspase 3
Cell Death
Cell Hypoxia
Cytoprotection
Glucose
Hippocampus
Hydroxyeicosatetraenoic Acids
Neuroprotective Agents
Rats
Rats, Sprague-Dawley
Superoxides
Time Factors
Tissue Culture Techniques
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a