PHA-543613 Preserves Blood–Brain Barrier Integrity After Intracerebral Hemorrhage in Mice
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.
- Received December 10, 2012.
- Accepted March 12, 2013.
- © 2013 American Heart Association, Inc.