title: PHA-543613 preserves blood-brain barrier integrity after intracerebral hemorrhage in mice.
abstract: OBJECTIVE
  Blood-brain barrier disruption and consequent vasogenic edema formation codetermine the clinical course of intracerebral hemorrhage (ICH). This study examined the effect of PHA-543613, a novel α7 nicotinic acetylcholine receptor agonist, on blood-brain barrier preservation after ICH.
  
  
  METHODS
  Male CD-1 mice, subjected to intrastriatal blood infusion, received PHA-543613 alone or in combination with α7 nicotinic acetylcholine receptor antagonist methyllycaconitine or phosphatidylinositol 3-kinase inhibitor wortmannin.
  
  
  RESULTS
  PHA-543613 alone, but not in combination with methyllycaconitine or wortmannin, inhibited glycogen synthase kinase-3β, thus, stabilizing β-catenin and tight junction proteins, which was paralleled by improved blood-brain barrier stability and ameliorated neurofunctional deficits in ICH animals.
  
  
  CONCLUSIONS
  PHA-543613 preserved blood-brain barrier integrity after ICH, possibly through phosphatidylinositol 3-kinase-Akt-induced inhibition of glycogen synthase kinase-3β and β-catenin stabilization.
authors.affiliation: Department of Neurosurgery, Loma Linda University, Loma Linda, CA 92354, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Krafft
authors.forename: Basak
authors.initials: B
authors.lastname: Caner
authors.forename: Damon
authors.initials: D
authors.lastname: Klebe
authors.forename: William B
authors.initials: WB
authors.lastname: Rolland
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002543:Cerebral Hemorrhage / Q000378:metabolism / Q000503:physiopathology*; D062465:Claudin-3 / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000077191:Wortmannin; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000730:Androstadienes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D062465:Claudin-3; C513163:N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D051176:beta Catenin; C054634:methyllycaconitine; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000157:Aconitine; D000077191:Wortmannin
keywords: PHA-543613; blood–brain barrier; intracerebral hemorrhage; mice; α7 nicotinic acetylcholine receptor