CYCLO-OXYGENASE-2 GENE-EXPRESSION IN NEURONS CONTRIBUTES TO ISCHEMIC BRAIN-DAMAGE

Cyclo-oxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synth esis, is induced during inflammation and participates in inflammation- mediated cytotoxicity. Cerebral ischemia is followed by an inflammator y reaction that plays a role in the evolution of the tissue damage. We studied whether COX-2 is induced after cerebral ischemia and if so, w hether such expression contributes to ischemic brain damage. The middl e cerebral artery was occluded in rats, and the ischemic area was samp led for analysis 3-96 hr later. COX-2 mRNA was determined by the compe titive reverse-transcription PCR. COX-2 mRNA was upregulated in the is chemic hemisphere, but not contralaterally, beginning 6 hr after ische mia. The upregulation reached a maximum at 12 hr, at which time a five fold induction of the message occurred. Twenty-four hours after ischem ia, the concentration of prostaglandin E-2 was elevated in the injured brain by 292+/-57% (n=6). COX-2 immunoreactivity was observed in neur ons at the medial edge of the ischemic area. Administration of the COX -2 inhibitor NS-398 attenuated the elevation in prostaglandin E-2 in t he postischemic brain and reduced the volume of the infarct by 29+/-6% (p <0.05). Thus, cerebral ischemia leads to upregulation of COX-2 mes sage, protein, and reaction products in the injured hemisphere, The da ta implicate COX-2 in the mechanisms of delayed neuronal death al the infarct border and provide the rationale for neuroprotective strategie s employing COX-2 inhibitors.