Expression of cyclooxygenase-2 mRNA after global ischemia is regulated by AMPA receptors and glucocorticoids

Background and Purpose-Cyclooxygenase-2 (COX-2) is implicated in ischemic n euronal death. In focal ischemia, its mRNA induction is mediated through N- methyl-D-aspartic acid (NMDA) receptors and phospholipase A?, Because mecha nisms of neuronal death involving COX-2 in global ischemia are unclear, we studied the time course and regulation of COX-2 expression in rat brain glo bal ischemia. Methods-Global ischemia was induced by a dr-vessel occlusion method. COX-2 mRNA levels were demonstrated with in situ hybridization and COX-2 protein with immunocytochemistry. Several animals were pretreated with MK-801, an N MDA receptor antagonist; 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxal ine (NBQX), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AM PA) receptor antagonist; and dexamethasone. Results-In the cortex, the CA3 hippocampal region and dentate gyrus express ion of COX-2 mRNA peaked at 4 to 8 hours, while in the CA1 region COX-2 mRN A levels were high at 4 to 24 hours. COX-2 protein was induced in the corre sponding regions at 12 to 24 hours, but in the CA1 neurons the protein was still seen at 3 days. COX-2 mRNA induction in the cortex was inhibited by N BQX and dexamethasone and in CAI neurons was inhibited by NBQX. MK-801 did not suppress COX-2 induction. Conclusions-COX-2 is differentially induced in the cortex and hippocampal s tructures after global ischemia. The prolonged COX-2 expression in the vuln erable CA1 neurons is regulated by AMPA receptors, suggesting that COX-2 ex pression is likely to be associated with AMPA receptor-mediated neuronal de ath in global ischemia, Glucocorticoids may not be efficiently used to inhi bit ischemia-induced COX-2 expression in the hippocampus.