title: Genetic deletion of the prostaglandin E2 E prostanoid receptor subtype 3 improves anatomical and functional outcomes after intracerebral hemorrhage.
abstract: Intracerebral hemorrhage (ICH) is a stroke subtype associated with high mortality and morbidity. Following ICH, excitotoxicity and inflammation significantly contribute to secondary brain injury and poor outcomes. Prostaglandin E2 (PGE2 ) levels rise locally with insult to the nervous system, and PGE2 is known to modulate these processes mainly through its E prostanoid (EP) receptors, EP1-4. EP receptor subtype 3 (EP3) is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE2 -EP3 axis exacerbates excitotoxicity and ischemic stroke outcomes. This study aimed to investigate the contribution of this pathway in modulating anatomical outcomes and functional recovery following ICH. Genetic deletion of EP3 resulted in 48.2 ± 7.3% less ICH-induced brain injury (P < 0.005) and improved functional recovery (P < 0.05), as identified by neurological deficit scoring. To start investigating the mechanisms involved in neuroprotection with impaired PGE2 -EP3 signaling, histological staining was performed to evaluate blood and ferric iron accumulation, neuroinflammation, blood-brain barrier dysfunction, and peripheral neutrophil infiltration. After ICH, EP3 knockout mice demonstrated 49.5 ± 8.8% and 42.8 ± 13.1% less blood (P < 0.01) and ferric iron (P < 0.05), respectively. Furthermore, EP3 knockout mice had significantly reduced astrogliosis, microglial activation, blood-brain barrier breakdown, and neutrophil infiltration. Collectively, these results suggest an injurious role for the PGE2 -EP3 signaling axis in modulating brain injury, inflammation, and neurological functional recovery after ICH. Modulation of the PGE2 -EP3 signaling axis may represent a putative therapeutic avenue for the treatment of ICH.
authors.affiliation: Department of Anesthesiology, University of Florida, 1275 Center Drive, Gainesville, FL, 32610-0159, USA.|Department of Neuroscience, University of Florida, 1275 Center Drive, Gainesville, FL, 32610-0159, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Leclerc
authors.affiliation: Department of Anesthesiology, University of Florida, 1275 Center Drive, Gainesville, FL, 32610-0159, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Lampert
authors.affiliation: Department of Anesthesiology, University of Florida, 1275 Center Drive, Gainesville, FL, 32610-0159, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Diller
authors.affiliation: Department of Anesthesiology, University of Florida, 1275 Center Drive, Gainesville, FL, 32610-0159, USA.|Department of Neuroscience, University of Florida, 1275 Center Drive, Gainesville, FL, 32610-0159, USA.|Departments of Neurology, Psychiatry and Pharmaceutics, University of Florida, 1275 Center Drive, Gainesville, FL, 32610-0159, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Doré
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D005911:Gliosis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism / Q000473:pathology
chemical_list: D058308:Receptors, Prostaglandin E, EP3 Subtype
keywords: gliosis; iron; mouse; neuroinflammation; neuroprotection; stroke
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