Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia.
The inducible isoform of the enzyme cyclooxygenase-2 (COX2) is an immediate early gene induced by synaptic activity in the brain. COX2 activity is an important mediator of inflammation, but it is not known whether COX2 activity is pathogenic in brain. To study the role of COX2 activity in ischemic injury in brain, expression of COX2 mRNA and protein and the effect of treatment with a COX2 inhibitor on neuronal survival in a rat model of global ischemia were determined. Expression of both COX2 mRNA and protein was increased after ischemia in CA1 hippocampal neurons before their death. There was increased survival of CA1 neurons in rats treated with the COX2-selective inhibitor SC58125 [1-[(4-methylsulfonyl) phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole] before or after global ischemia compared with vehicle controls. Furthermore, hippocampal prostaglandin E2 concentrations 24 h after global ischemia were decreased in drug-treated animals compared with vehicle-treated controls. These results suggest that COX2 activity contributes to CA1 neuronal death after global ischemia.
Nakayama
M
M
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Uchimura
K
K
Zhu
R L
RL
Nagayama
T
T
Rose
M E
ME
Stetler
R A
RA
Isakson
P C
PC
Chen
J
J
Graham
S H
SH
D000818:Animals; D016923:Cell Death; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D007150:Immunohistochemistry; D007511:Ischemia / Q000201:enzymology / Q000473:pathology*; D007527:Isoenzymes / Q000187:drug effects* / Q000235:genetics; D008297:Male; D009474:Neurons / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D012333:RNA, Messenger; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases