title: Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice.
abstract: Inflammatory responses mediated by prostaglandins such as PGE2may contribute to secondary brain injury after intracerebral hemorrhage (ICH). However, the cell-specific signaling by PGE2receptor EP2 differs depending on whether the neuropathic insult is acute or chronic. Using genetic and pharmacologic approaches, we investigated the role of EP2 receptor in two mouse models of ICH induced by intrastriatal injection of collagenase or autologous arterial whole blood. We used middle-aged male mice to enhance the clinical relevance of the study. EP2 receptor was expressed in neurons but not in astrocytes or microglia after collagenase-induced ICH. Brain injury after collagenase-induced ICH was associated with enhanced cellular and molecular inflammatory responses, oxidative stress, and matrix metalloproteinase (MMP)-2/9 activity. EP2 receptor deletion exacerbated brain injury, brain swelling/edema, neuronal death, and neurobehavioral deficits, whereas EP2 receptor activation by the highly selective agonist AE1-259-01 reversed these outcomes. EP2 receptor deletion also exacerbated brain edema and neurologic deficits in the blood ICH model. These findings support the premise that neuronal EP2 receptor activation by PGE2protects brain against ICH injury in middle-aged mice through its anti-inflammatory and anti-oxidant effects and anti-MMP-2/9 activity. PGE2/EP2 signaling warrants further investigation for potential use in ICH treatment.
authors.affiliation: Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China wuher2009@hotmail.com.
authors.forename: He
authors.initials: H
authors.lastname: Wu
authors.affiliation: Stroke Center, Stroke Screening and Intervention Base, Changhai Hospital, Second Military Medical University, Shanghai, China.|Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jieru
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Qingwu
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA jwang79@jhmi.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000375:Aging; D000818:Animals; D001930:Brain Injuries / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000150:complications*; D017364:Collagenases / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism / Q000502:physiology*
chemical_list: D018696:Neuroprotective Agents; D058307:Receptors, Prostaglandin E, EP2 Subtype; D017364:Collagenases
keywords: High-mobility group box 1; PGE2; inflammation; prostaglandin receptor