title: A glutamate receptor antagonist, S-4-carboxyphenylglycine (S-4-CPG), inhibits vasospasm after subarachnoid hemorrhage in haptoglobin 2-2 mice [corrected].
abstract: BACKGROUND
  Vasospasm contributes to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Glutamate concentrations increase after SAH and correlate with vasospasm in experimental SAH. The haptoglobin (Hp) 2-2 genotype is associated with higher risk of vasospasm after SAH. We tested the efficacy of (S)-4-carboxyphenylglycine (S-4-CPG), a metabotropic glutamate receptor inhibitor, for the treatment of vasospasm after SAH in Hp 2-2 and Hp 1-1 mice.
  
  
  OBJECTIVE
  To evaluate the effect on vasospasm and neurobehavioral scores after SAH of systemic S-4-CPG, as well as its toxicity, and phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in Hp 2-2 mice.
  
  
  METHODS
  Western blot was used to assess changes in VASP phosphorylation in response to glutamate with and without S-4-CPG. A pharmacokinetics study was done to evaluate S-4-CPG penetration through the blood-brain barrier in vivo. Toxicity was assessed by administering increasing S-4-CPG doses. Efficacy of S-4-CPG assessed the effect of S-4-CPG on lumen patency of the basilar artery and animal behavior after SAH in Hp 1-1 and Hp 2-2 mice. Immunohistochemistry was used to evaluate the presence of neutrophils surrounding the basilar artery after SAH.
  
  
  RESULTS
  Exposure of human brain microvascular endothelial cells to glutamate decreased phosphorylation of VASP, but glutamate treatment in the presence of S-4-CPG maintains phosphorylation of VASP. S-4-CPG crosses the blood-brain barrier and was not toxic to mice. S-4-CPG treatment significantly prevents vasospasm after SAH. S-4-CPG administered after SAH resulted in a trend toward improvement of animal behavior.
  
  
  CONCLUSIONS
  S-4-CPG prevents vasospasm after experimental SAH in Hp2-2 mice. S-4-CPG was not toxic and is a potential therapeutic agent for vasospasm after SAH.
authors.affiliation: Department of †Neurosurgery; ‡Oncology Center-Chemical Therapeutics, The Johns Hopkins University School of Medicine, Baltimore, Maryland; §Technion Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Tomas
authors.initials: T
authors.lastname: Garzon-Muvdi
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pradilla
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Ruzevick
authors.forename: Matthew
authors.initials: M
authors.lastname: Bender
authors.forename: Lindsay
authors.initials: L
authors.lastname: Edwards
authors.forename: Rachel
authors.initials: R
authors.lastname: Grossman
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Gregory
authors.initials: G
authors.lastname: Riggins
authors.forename: Andrew
authors.initials: A
authors.lastname: Levy
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Tamargo
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005838:Genotype; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006242:Haptoglobins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000235:genetics; D053719:Tandem Mass Spectrometry; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D001565:Benzoates; D015815:Cell Adhesion Molecules; D006242:Haptoglobins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D018094:Receptors, Metabotropic Glutamate; D000098662:Vasodilator-Stimulated Phosphoprotein; C079693:4-carboxyphenylglycine; D005998:Glycine