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The Journal of Neuroscience, January 7, 2004, 24(1):257-268; doi:10.1523/JNEUROSCI.4485-03.2004
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Neurobiology of Disease
Neuroprotective Function of the PGE2 EP2 Receptor in Cerebral Ischemia
Louise McCullough,1 Liejun Wu,1 Norman Haughey,1 Xibin Liang,1 Tracey Hand,1 Qian Wang,1 Richard M. Breyer,3 andKatrin Andreasson1,2 Departments of 1Neurology and 2Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and 3Department of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE2, a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMP-dependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE2 receptor subtype in brain that may provide a target for therapeutic intervention.
Key words: hippocampus; cerebral cortex; neuroprotection; prostaglandin; PGE2; EP2 receptor; cAMP; stroke
Received July 3, 2003; revised November 5, 2003; accepted November 7, 2003.
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