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Cyclooxygenase-2 Induction in Cerebral Cortex: An Intracellular Response to Synaptic Excitation

Authors


Address correspondence and reprint requests to Dr. J. de Belleroche at Department of Biochemistry, Charing Cross and Westminster Medical School, Fulham Palace Road, London, W6 8RF, U.K.

Abstract

Abstract: We have characterised the induction of the mitogen-inducible form of cyclooxygenase, COX-2, in the rat cerebral cortex in response to excitotoxin injection into the nucleus basalis. This model is associated with intense stimulation of the ascending pathway to the cerebral cortex, seizure activity, and subsequent ipsilateral cortical induction of various immediate early genes (IEGs), including c-fos, c-jun, and zif268, and ornithine decarboxylase enzyme activity and mRNA, all of which processes are sensitive to treatment with the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. In this study we show that excitotoxin injection also causes a marked induction of COX-2 mRNA in ipsilateral cortex detectable at 1 h and peaking at 4 h, where COX-2 mRNA levels were 19 times those in unoperated animals. Levels of COX-2 mRNA remained significantly elevated at 24 h. The early induction of COX-2 at 1 h was also seen in sham-operated animals, but at 4 h the COX-2 mRNA level was significantly increased (4.4-fold) in animals injected with excitotoxin compared with sham-operated animals. The induction at this time point (4 h) was explored pharmacologically and found to be significantly attenuated by treatment with MK-801 (1.5 mg/kg), lamotrigine (10 mg/kg), which prevents presynaptic glutamate release by blocking voltage-sensitive Na+ channels, and the glucocorticoid dexamethasone (3 mg/kg), which has an indirect inhibitory effect on phospholipase A2 and COX activity. These results demonstrate that the induction of COX-2 mRNA occurs by two distinct mechanisms: the rapid and transient response to tissue damage and a second delayed and more substantial response, which is initiated by excitotoxin stimulation and is mediated by presynaptic glutamate release, NMDA receptor activation, and subsequent phospholipase A2 activity. We propose a model to demonstrate the similarities between COX-2 and IEG mRNA induction and highlight possible mechanistic differences in the nature of the induction by the phospholipase A2 pathway.

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