CYCLOOXYGENASE-2 INDUCTION IN CEREBRAL-CORTEX - AN INTRACELLULAR RESPONSE TO SYNAPTIC EXCITATION

We have characterised the induction of the mitogen-inducible form of c yclooxygenase, COX-2, in the rat cerebral cortex in response to excito toxin injection into the nucleus basalis. This model is associated wit h intense stimulation of the ascending pathway to the cerebral cortex, seizure activity, and subsequent ipsilateral cortical induction of va rious immediate early genes (IEGs), including c-fos, c-jun, and zif268 , and ornithine decarboxylase enzyme activity and mRNA, all of which p rocesses are sensitive to treatment with the N-methyl-D-aspartate (NMD A) 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 w ere 19 times those in unoperated animals. Levels of COX-2 mRNA remaine d 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 leve l was significantly increased (4.4-fold) in animals injected with exci totoxin compared with sham-operated animals. The induction at this tim e point (4 h) was explored pharmacologically and found to be significa ntly attenuated by treatment with MK-801 (1.5 mg/kg), lamotrigine (10 mg/kg), which prevents presynaptic glutamate release by blocking volta ge-sensitive Na+ channels, and the glucocorticoid dexamethasone (3 mg/ kg), which has an indirect inhibitory effect on phospholipase A(2) and COX activity. These results demonstrate that the induction of COX-2 m RNA occurs by two distinct mechanisms: the rapid and transient respons e to tissue damage and a second delayed and more substantial response, which is initiated by excitotoxin stimulation and is mediated by pres ynaptic glutamate release, NMDA receptor activation, and subsequent ph ospholipase A(2) activity. We propose a model to demonstrate the simil arities between COX-2 and IEG mRNA induction and highlight possible me chanistic differences in the nature of the induction by the phospholip ase A(2) pathway.