title: Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke.
abstract: Cyclooxygenase-2 (COX-2) is activated in response to ischemia and significantly contributes to the neuroinflammatory process. Accumulation of COX-2-derived prostaglandin E2 (PGE2) parallels the substantial increase in stroke-mediated blood-brain barrier (BBB) breakdown. Disruption of the BBB is a serious consequence of ischemic stroke, and is mainly mediated by matrix metalloproteinases (MMPs). This study aimed to investigate the role of PGE2 EP1 receptor in neurovascular injury in stroke. We hypothesized that pharmacological blockade or genetic deletion of EP1 protects against BBB damage and hemorrhagic transformation by decreasing the levels and activity of MMP-3 and MMP-9. We found that post-ischemic treatment with the EP1 antagonist, SC-51089, or EP1 genetic deletion results in a significant reduction in BBB disruption and reduced hemorrhagic transformation in an experimental model of transient focal cerebral ischemia. These neurovascular protective effects of EP1 inactivation are associated with a significant reduction in MMP-9/-3, less peripheral neutrophil infiltration, and a preservation of tight junction proteins (ZO-1 and occludin) composing the BBB. Our study identifies the EP1 signaling pathway as an important link between neuroinflammation and MMP-mediated BBB breakdown in ischemic stroke. Targeting the EP1 receptor could represent a novel approach to diminish the devastating consequences of stroke-induced neurovascular damage.
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Frankowski
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: DeMars
authors.affiliation: Department of Anesthesiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Abdullah S
authors.initials: AS
authors.lastname: Ahmad
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Hawkins
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Changjun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Leclerc
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.|Department of Anesthesiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Doré
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Candelario-Jalil
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020520:Brain Infarction / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D020556:Neutrophil Infiltration; D010077:Oxazepines / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D062725:Tight Junction Proteins / Q000378:metabolism
chemical_list: D006834:Hydrazines; D010077:Oxazepines; D058306:Receptors, Prostaglandin E, EP1 Subtype; D062725:Tight Junction Proteins; C086836:SC 51089; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9