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The Janus Face of Cyclooxygenase-2 in Ischemic Stroke: Shifting Toward Downstream Targets

The rate-limiting enzyme for prostanoid synthesis cyclooxygenase-2 (COX-2) has been implicated in the basic mechanisms of several brain diseases, including stroke, multiple sclerosis and neurodegenerative diseases.1 The approval by the Food and Drug Administration (FDA) of highly selective COX-2 inhibitors for the treatment of pain and rheumatoid arthritis (RA) raised the possibility that these agents could also be used in the treatment of neurological diseases including stroke. However, the occurrence of serious cardiovascular complications in patients receiving COX-2 inhibitors has led to the recent withdrawal from the market of a popular COX-2 inhibitor and has called for a re-evaluation of the therapeutic potential of these drugs. In this article, we briefly review the role of COX-2 in ischemic brain injury and re-examine the validity of the COX-2 pathway as a therapeutic target for ischemic stroke.

COX enzymes catalyze the conversion of arachidonic acid into prostaglandin H2 (PGH2; Figure).2 Arachidonic acid, produced by the breakdown of membrane phospholipids, is metabolized by COX into PGH2 in a 2-step reaction in which the free radical superoxide is also produced.2 Three isoforms of COX have been described. COX-1 is present in most cells and is involved in normal cellular physiology, such as gastric secretion and platelet function.2 COX-2 is expressed constitutively in some organs, such as brain, but is markedly upregulated by a wide variety of stimuli, most notably inflammatory mediators.2 COX-3, a splice variant of COX-1, is highly sensitive to inhibition by acetaminophen and is most abundant in heart and brain.3 The COX reaction product PGH2 is converted into 5 different prostanoids by a corresponding number of isomerases (Figure), the distribution of which is cell and organ specific.2 Thus, PGH2 can give rise to different prostanoids depending on the …