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Vol. 293, Issue 2, 417-425, May 2000
Department of Pharmacology, Program in Neuroscience, University of
Connecticut Health Center, Farmington, Connecticut
Cyclooxygenase isozymes (COX-1 and COX-2) are found to be
constitutively expressed in brain, with neuronal expression of COX-2 being rapidly induced after numerous insults, including cerebral ischemia. Because overactivation of
N-methyl-D-aspartate (NMDA) receptors has
been implicated in the cell loss associated with ischemia, we
characterized the expression of the COX isozymes in murine mixed
cortical cell cultures and used isozyme-selective inhibitors to
determine their relative contribution to NMDA receptor-stimulated prostaglandin (PG) production and excitotoxic neuronal cell death. Immunocytochemical analysis of mixed cortical cell cultures revealed that COX-2 expression was restricted to neurons, whereas COX-1 was
expressed in both neurons and astrocytes. Brief exposure to NMDA (5 min; 100 µM) elicited a time-dependent accumulation of PGs in the
culture medium that preceded neuronal cell death and correlated with
the induction of COX-2 mRNA. COX-1 expression remained unchanged.
Flurbiprofen, a nonselective COX-1/COX-2 inhibitor, blocked
NMDA-stimulated PG production and attenuated neuronal death in a
concentration-dependent manner. Similar results were obtained with the
specific COX-2 inhibitor NS-398 (10-30 µM) but not with the
selective COX-1 inhibitor valeryl salicylate (10-300 µM). Inhibition
of total constitutive COX activity with aspirin (100 µM, 1.5 h)
before NMDA exposure did not prevent subsequent NMDA-mediated neuronal
cell death. However, neuronal injury in aspirin-pretreated cultures was
attenuated by flurbiprofen administration after NMDA exposure. Finally,
the protection afforded by COX-2 inhibition was specific for NMDA
because neither flurbiprofen nor NS-398 protected neurons against
kainate-mediated neurotoxicity. Together, these results support the
conclusion that newly synthesized COX-2 protein contributes to
NMDA-induced neuronal injury.
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