Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage.
Cyclo-oxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, is induced during inflammation and participates in inflammation-mediated cytotoxicity. Cerebral ischemia is followed by an inflammatory 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, whether such expression contributes to ischemic brain damage. The middle cerebral artery was occluded in rats, and the ischemic area was sampled for analysis 3-96 hr later. COX-2 mRNA was determined by the competitive reverse-transcription PCR. COX-2 mRNA was upregulated in the ischemic hemisphere, but not contralaterally, beginning 6 hr after ischemia. The upregulation reached a maximum at 12 hr, at which time a fivefold induction of the message occurred. Twenty-four hours after ischemia, the concentration of prostaglandin E2 was elevated in the injured brain by 292 +/- 57% (n = 6). COX-2 immunoreactivity was observed in neurons at the medial edge of the ischemic area. Administration of the COX-2 inhibitor NS-398 attenuated the elevation in prostaglandin E2 in the postischemic brain and reduced the volume of the infarct by 29 +/- 6% (p < 0.05). Thus, cerebral ischemia leads to upregulation of COX-2 message, protein, and reaction products in the injured hemisphere. The data implicate COX-2 in the mechanisms of delayed neuronal death at the infarct border and provide the rationale for neuroprotective strategies employing COX-2 inhibitors.
Nogawa
S
S
Laboratory of Cerebrovascular Biology and Stroke, Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Zhang
F
F
Ross
M E
ME
Iadecola
C
C
D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002245:Carbon Dioxide / Q000097:blood; D002536:Cerebral Arteries; D051546:Cyclooxygenase 2; D017931:DNA Primers; D004790:Enzyme Induction; D007839:Functional Laterality; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000097:blood / Q000201:enzymology / Q000473:pathology*; D007527:Isoenzymes / Q000096:biosynthesis*; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010100:Oxygen / Q000097:blood; D016133:Polymerase Chain Reaction / Q000379:methods; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D017931:DNA Primers; D007527:Isoenzymes; D012333:RNA, Messenger; D002245:Carbon Dioxide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010100:Oxygen