Prostaglandins (PGs) and thromboxanes (TXs) have long been implicated in the pathogenesis of cerebral ischemic stroke. 1 However, because of the lack of appropriate investigative tools, their role in the mechanisms of the injury could not be clearly defined. The identification and cloning of distinct forms of cyclooxygenase (COX), a rate-limiting enzyme for prostanoid synthesis, has provided new experimental approaches and has revived the interest in the role of prostanoids in stroke and other brain diseases. 2 In this issue of Annals, Dore Β΄and colleagues, 3 used transgenic mice overexpressing COX-2 selectively in neurons to investigate the involvement of this enzyme in ischemic brain injury. They found that the brain damage produced by temporary occlusion of the middle cerebral artery is exacerbated in COX-2 transgenic mice, an effect associated with increased synthesis of prostanoids. A selective COX-2 inhibitor attenuated prostanoid synthesis both in wild-type and transgenic mice. Unexpectedly, however, COX-2 inhibition reduced brain damage in wild-type mice, but not in COX-2 transgenics. This surprising finding, while providing additional evidence for the deleterious potential of COX-2, unveils a new aspect of role of COX-2 in brain injury.
Three isoforms of COX have been identified: COX-1, COX-2, and the COX-1 splice variant COX-3. 4 COX-1 and COX-2 have been studied most extensively. COX-1 is constitutively expressed in many organs and is thought to synthesize prostanoids involved in normal cellular activities, such as gastric secretion, endothelial function, and platelet aggregation. 5 COX-2, although constitutively active in some organs such as brain and kidney, is highly inducible in response to a wide variety of stimuli including inflammatory mediators and growth factors. 2 In brain, COX-2 is normally present in glutamatergic synapses and its expression and activity are regulated by synaptic activity. 6 For example, COX-2 reaction products are involved in the increase in cerebral blood flow produced by functional activation. 7 In brain diseases such as ischemic stroke, COX-2 is transiently upregulated, and its reaction products are thought to contribute to tissue damage (Fig) . COX-2-derived prostanoids that could play a role include PGE2, which enhances glutamate excitotoxicity, TXA2, which promotes vasoconstriction and platelet aggrega-