Journal
NEUROSCIENCE
Volume 145, Issue 3, Pages 931-941Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2006.12.063
Keywords
neuroprotection; ERK1/2; mixed cortical neuron/astrocyte cell cultures; organotypic hippocampal slice cultures; ischemia; oxygen/glucose deprivation
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Funding
- NINDS NIH HHS [P01 NS005820-390027, RF1 NS034773, R01 NS054147, R01 NS054147-01A1, R29 NS034773, R01 NS045676, NS34773, NS045676, R01 NS034773-09, R01 NS045676-03, NS05820, R01 NS034773, NS054147, P01 NS005820] Funding Source: Medline
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The signaling pathway of cyclooxygenase-2 (COX-2) induction following ischemic preconditioning (IPC) in brain remains undefined. To determine role of COX-2 in ischemic preconditioning, we used two in vitro models: mixed cortical neuron/astrocyte cell cultures and organotypic hippocampal slice cultures. We simulated IPC by exposing cell or slice cultures to 1 h or 15 min of oxygen/glucose deprivation (OGD), respectively, 48 h prior to ischemia. To mimic ischemia in vitro, we exposed cell or slice cultures to OGD of 4 h or 40 min, respectively. In cell cultures, these experiments revealed that COX-2 induction peaked at 24 In following IPC in cell culture. Inhibition of COX-2 activation with 50 mu M NS-398 (a COX-2 selective inhibitor) abolished IPC-mediated neuroprotection in both in vitro models. Next, we tested whether e protein kinase C (EPKC) and extracellular signal regulated kinase 1/2 (ERK1/2) activation was involved in IPC-mediated neuroprotection and COX-2 expression in cell culture. Cell cultures were treated with an epsilon PKCspecific activating peptide (psi epsilon RACK, 100 nM) for 1 h, and 48 h later were exposed to OGD. epsilon PKC activation increased ERK1/2 phosphorylation and COX-2 induction and conferred neuroprotection similar to IPC. Additionally, inhibition of either EPKC or ERK1/2 activation abolished COX-2 expression and neuroprotection due to ischemic preconditioning. These results demonstrate a crucial role for the epsilon PKC -> ERK1/2 -> COX-2 pathway in the induction of neuroprotection via ischemic preconditioning. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.
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