Expression of cyclooxygenase-2 mRNA after global ischemia is regulated by AMPA receptors and glucocorticoids.
OBJECTIVE
Cyclooxygenase-2 (COX-2) is implicated in ischemic neuronal death. In focal ischemia, its mRNA induction is mediated through N-methyl-D-aspartic acid (NMDA) receptors and phospholipase A(2). Because mechanisms 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 global ischemia.


METHODS
Global ischemia was induced by a 4-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 NMDA receptor antagonist; 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist; and dexamethasone.


RESULTS
In the cortex, the CA3 hippocampal region and dentate gyrus expression of COX-2 mRNA peaked at 4 to 8 hours, while in the CA1 region COX-2 mRNA levels were high at 4 to 24 hours. COX-2 protein was induced in the corresponding 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 NBQX and dexamethasone and in CA1 neurons was inhibited by NBQX. MK-801 did not suppress COX-2 induction.


CONCLUSIONS
COX-2 is differentially induced in the cortex and hippocampal structures after global ischemia. The prolonged COX-2 expression in the vulnerable CA1 neurons is regulated by AMPA receptors, suggesting that COX-2 expression is likely to be associated with AMPA receptor-mediated neuronal death in global ischemia. Glucocorticoids may not be efficiently used to inhibit ischemia-induced COX-2 expression in the hippocampus.
Koistinaho
J
J
A.I. Virtanen Institute for Molecular Sciences, University of Kuopio Finland. jari.koistinaho@uku.fi
Koponen
S
S
Chan
P H
PH
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology*; D013997:Time Factors; D014018:Tissue Distribution
D018691:Excitatory Amino Acid Antagonists; D005938:Glucocorticoids; D007527:Isoenzymes; D011810:Quinoxalines; D012333:RNA, Messenger; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D003907:Dexamethasone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases