Nature Medicine
- 12, 225 - 229 (2006)
Published online: 6 January 2006; | doi:10.1038/nm1362
Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicityTakayuki Kawano1, 2, Josef Anrather1, 2, Ping Zhou1, Laibaik Park1, Gang Wang1, Kelly A Frys1, Alexander Kunz1, Sunghee Cho1, Marcello Orio1 & Costantino Iadecola11
Division of Neurobiology, 411 East 69th St., Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA. 2
These authors contributed equally to this work.
Correspondence should be addressed to Costantino Iadecola coi2001@med.cornell.edu Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, has been implicated in the neurotoxicity resulting from hypoxia-ischemia, and its inhibition has therapeutic potential for ischemic stroke. However, COX-2 inhibitors increase the risk of cardiovascular complications. We therefore sought to identify the downstream effectors of COX-2 neurotoxicity, and found that prostaglandin E2 EP1 receptors are essential for the neurotoxicity mediated by COX-2–derived prostaglandin E2. EP1 receptors disrupt Ca2+ homeostasis by impairing Na+-Ca2+ exchange, a key mechanism by which neurons cope with excess Ca2+ accumulation after an excitotoxic insult. Thus, EP1 receptors contribute to neurotoxicity by augmenting the Ca2+ dysregulation underlying excitotoxic neuronal death. Pharmacological inhibition or gene inactivation of EP1 receptors ameliorates brain injury induced by excitotoxicity, oxygen glucose deprivation and middle cerebral artery (MCA) occlusion. An EP1 receptor inhibitor reduces brain injury when administered 6 hours after MCA occlusion, suggesting that EP1 receptor inhibition may be a viable therapeutic option in ischemic stroke.
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