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 PGE2 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. Ann Neurol 2003