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.