Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction.
Increases in COX-2 enzymatic activity and prostaglandin production have been associated with neuronal injury in both acute and age-related degenerative neurological diseases. In this study, we tested the effects of increased COX-2 activity in a model of transient focal ischemia using a transgenic mouse model in which human COX-2 is constitutively expressed selectively in neurons of the striatum, cerebral cortex, and hippocampus. These COX-2 transgenic mice harbor elevated levels of PGE(2) that are 10-fold higher than nontransgenic levels. A significant increase in infarct volume was observed after middle cerebral artery occlusion with 4 days of reperfusion in COX-2 transgenic mice as compared with nontransgenic littermates. Pretreatment of nontransgenic mice with the selective COX-2 inhibitor SC58236 resulted in a significant reduction of infarct volume in nontransgenic mice, consistent with previous pharmacological studies. However, transgenic COX-2 mice treated with SC58236 did not show a significant reduction. This suggests that chronic increases in COX-2 expression and enzymatic activity, which can occur in aging and in pathological states characterized by oxidative stress and chronic inflammatory processes, can lead to downstream cellular changes that have a negative impact on neuronal survival in cerebrovascular disease.
Doré
Sylvain
S
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Otsuka
Takashi
T
Mito
Toshiaki
T
Sugo
Nubuo
N
Hand
Tracey
T
Wu
Liejun
L
Hurn
Patricia D
PD
Traystman
Richard J
RJ
Andreasson
Katrin
K
D000818:Animals; D001784:Blood Gas Analysis; D015153:Blotting, Western; D001831:Body Temperature / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000502:physiology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000502:physiology; D011720:Pyrazoles / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use; D000096926:Benzenesulfonamides
D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human