Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Biochemistry, Charing Cross and Westminster Medical School, London, England.
J
J
Adams
Y
Y
Collaço-Moraes
J
J
de Belleroche
D000818:Animals; D001483:Base Sequence; D003907:Dexamethasone / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D000077213:Lamotrigine; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012045:Regulatory Sequences, Nucleic Acid; D013377:Substantia Innominata / Q000187:drug effects / Q000201:enzymology*; D009435:Synaptic Transmission / Q000502:physiology*; D014227:Triazines / Q000494:pharmacology
D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D003907:Dexamethasone; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D007608:Kainic Acid; D000077213:Lamotrigine