title: Signaling via the prostaglandin E₂ receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia.
abstract: Stroke is the third leading cause of death in the United States. Fewer than 5% of patients benefit from the only intervention approved to treat stroke. Thus, there is an enormous need to identify new therapeutic targets. The role of inducible cyclooxygenase (COX-2) activity in stroke and other neurologic diseases is complex, as both activation and sustained inhibition can engender cerebral injury. Whether COX-2 induces cerebroprotective or injurious effects is probably dependent on which downstream prostaglandin receptors are activated. Here, we investigated the function of the PGE2 receptor EP4 in a mouse model of cerebral ischemia. Systemic administration of a selective EP4 agonist after ischemia reduced infarct volume and ameliorated long-term behavioral deficits. Expression of EP4 was robust in neurons and markedly induced in endothelial cells after ischemia-reperfusion, suggesting that neuronal and/or endothelial EP4 signaling imparts cerebroprotection. Conditional genetic inactivation of neuronal EP4 worsened stroke outcome, consistent with an endogenous protective role of neuronal EP4 signaling in vivo. However, endothelial deletion of EP4 also worsened stroke injury and decreased cerebral reperfusion. Systemic administration of an EP4 agonist increased levels of activated eNOS in cerebral microvessels, an effect that was abolished with conditional deletion of endothelial EP4. Thus, our data support the concept of targeting protective prostaglandin receptors therapeutically after stroke.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Xibin
authors.initials: X
authors.lastname: Liang
authors.forename: Lu
authors.initials: L
authors.lastname: Lin
authors.forename: Nathaniel S
authors.initials: NS
authors.lastname: Woodling
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Christoph
authors.initials: C
authors.lastname: Anacker
authors.forename: Tingting
authors.initials: T
authors.lastname: Pan
authors.forename: Milton
authors.initials: M
authors.lastname: Merchant
authors.forename: Katrin
authors.initials: K
authors.lastname: Andreasson
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control; D003517:Cyclopentanes / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008738:Methyl Ethers; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013864:Thioglycolates / Q000494:pharmacology
chemical_list: D003517:Cyclopentanes; D008738:Methyl Ethers; C461399:ONO-AE1-329; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013864:Thioglycolates