PHA-543613 preserves blood-brain barrier integrity after intracerebral hemorrhage in mice

Paul R. Krafft, Basak Caner, Damon Klebe, William B. Rolland, Jiping Tang, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND AND PURPOSE: 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.

Original languageEnglish
Pages (from-to)1743-1747
Number of pages5
JournalStroke
Volume44
Issue number6
DOIs
StatePublished - Jun 2013

ASJC Scopus Subject Areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Keywords

  • Blood-brain barrier
  • Intracerebral hemorrhage
  • Mice
  • PHA-543613
  • α7 nicotinic acetylcholine receptor
  • Claudin-3/metabolism
  • Receptors, Nicotinic/physiology
  • Phosphatidylinositol 3-Kinases/metabolism
  • Glycogen Synthase Kinase 3 beta
  • Male
  • Proto-Oncogene Proteins c-akt/metabolism
  • Glycogen Synthase Kinase 3/antagonists & inhibitors
  • Mice, Inbred Strains
  • Signal Transduction/drug effects
  • Aconitine/analogs & derivatives
  • Bridged Bicyclo Compounds, Heterocyclic/pharmacology
  • Animals
  • Blood-Brain Barrier/drug effects
  • beta Catenin/metabolism
  • Wortmannin
  • Cerebral Hemorrhage/metabolism
  • Androstadienes/pharmacology
  • Quinuclidines/pharmacology
  • Disease Models, Animal

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