Phospholipase A2 mediates ischemic injury in the hippocampus:: a regional difference of neuronal vulnerability

Although it is well known that the hippocampal CA1 subfield is highly vulnerable to ischemic injury, cellular mechanisms leading to this neuronal degeneration are not fully understood. Using organotypic cultures of rat hippocampal slices, we determined whether phospholipase A(2) (PLA(2)) is activated in response to ischemic conditions (OGD; oxygen and glucose deprivation). The PLA(2) activity in the pyramidal cell layer increased immediately following a 35-min exposure to OGD, which was likely to be mediated by selective activation of cytosolic Ca2+-dependent PLA(2) subtype (cPLA(2)). This enhancement lasted for at least 24 h. Interestingly, no apparent increase was detected in the dentate gyrus. Twenty-four hours after the OGD exposure, neuronal death was detected mainly in the CA1 region of hippocampal slices. To examine whether the PLA(2) activation is causally or protectively involved in the ischemic injury, we investigated the effect of pharmacological blockade of PLA(2) on the OGD-induced neuronal death. The PLA(2) inhibitor bromophenacyl bromide efficiently prevented the cell death in a concentration-dependent manner. Similar results were obtained for the selective cPLA(2) inhibitor AACOCF(3). However, the Ca2+-independent PLA(2) inhibitor bromoenol lactone and the secretory PLA(2) inhibitor LY311727 were virtually ineffective. These results suggest that cPLA(2) plays a causative role in the neuronal death following OGD exposure. Thus, the present study may provide novel therapeutic targets for the development of neuroprotective agents.