title: Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury.
abstract: Prostaglandin E2 EP3 receptor is the only prostaglandin E2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68(+) microglia, but increased the number of Ym-1(+) M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase-mediated cytotoxicity and proinflammatory responses.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Project Management, Discovery and Research, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA jwang79@jhmi.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced* / Q000209:etiology; D016923:Cell Death / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology*; D006629:Hirudins / Q000494:pharmacology; D007249:Inflammation; D051379:Mice; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013917:Thrombin / Q000008:administration & dosage / Q000009:adverse effects*; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D006629:Hirudins; D058308:Receptors, Prostaglandin E, EP3 Subtype; D054460:rho-Associated Kinases; D013917:Thrombin; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: Microglia; Rho-Rho kinase; matrix metalloproteinase-9; prostaglandin receptor; slice culture; thrombin