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(Stroke. 1999;30:1900-1906.)
© 1999 American Heart Association, Inc.

Original Contributions

Expression of Cyclooxygenase-2 mRNA After Global Ischemia Is Regulated by AMPA Receptors and Glucocorticoids

Jari Koistinaho, MD, PhD; Susanna Koponen, BS Pak H. Chan, PhD

From A.I. Virtanen Institute for Molecular Sciences, University of Kuopio (Finland) (J.K., S.K.); Department of Neurology, Kuopio University Hospital (Finland) (J.K.); and Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, Calif (J.K., S.K., P.H.C.).

Background and Purpose—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 A₂. 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 -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.

Editorial Comment

Chung Y. Hsu, MD, PhD, Guest Editor

Department of Neurology, Washington University School of Medicine, St Louis, Missouri

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