title: The neurorestorative benefit of GW3965 treatment of stroke in mice.
abstract: OBJECTIVE
  GW3965, a synthetic liver X receptor agonist, elevates high-density lipoprotein cholesterol and has antiatherosclerosis and anti-inflammation properties. We tested the hypothesis that GW3965 treatment of stroke increases vascular remodeling, promotes synaptic protein expression and axonal growth in the ischemic brain, and improves functional outcome in mice.
  
  
  METHODS
  Mice were subjected to transient middle cerebral artery occlusion and treated without or with different doses of GW3965 (5, 10, or 20 mg/kg) starting 24 hours after middle cerebral artery occlusion daily for 14 days. Neurological functional tests, blood high-density lipoprotein cholesterol measurement, and immunostaining were performed. Mouse brain endothelial cells, primary cultured artery explants, and primary cortical neurons cultures were also used in vitro.
  
  
  RESULTS
  GW3965 treatment of stroke significantly increased blood high-density lipoprotein cholesterol level, synaptic protein expression, axonal density, angiogenesis and arteriogenesis, and Angiopoietin1, Tie2, and occludin expression in the ischemic brain and improved functional outcome compared with middle cerebral artery occlusion control animals (n=10; P<0.05). In vitro, GW3965 and high-density lipoprotein cholesterol also significantly increased capillary-like tube formation and artery explant cell migration as well as neurite outgrowth. Inhibition of Angiopoietin-1 attenuated GW3965-induced tube-formation, artery cell migration, and neurite outgrowth (n=6 per group; P<0.05).
  
  
  CONCLUSIONS
  These data indicate, for the first time, that GW3965 promotes synaptic protein expression and axonal growth and increases vascular remodeling, which may contribute to improvement of functional outcome after stroke. Increasing Angiopoietin-1/Tie2 signaling activity may play an important role in GW3965-induced brain plasticity and neurological recovery from stroke.
authors.affiliation: Neurology Research, E&R Bldg., Room #3091, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cui
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Cui
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001565:Benzoates / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001596:Benzylamines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D016896:Treatment Outcome
chemical_list: D001565:Benzoates; D001596:Benzylamines; D008076:Cholesterol, HDL; C473027:GW 3965; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors