A glutamate receptor antagonist, S-4-carboxyphenylglycine (S-4-CPG), inhibits vasospasm after subarachnoid hemorrhage in haptoglobin 2 to 2 mice

Tomas Garzon-Muvdi, Gustavo Pradilla, Jacob J. Ruzevick, Matthew Bender, Lindsay Edwards, Rachel Grossman, Ming Zhao, Michelle A. Rudek, Gregory Riggins, Andrew Levy, Rafael J. Tamargo

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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. CONCLUSION:: 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.

Original languageEnglish (US)
Pages (from-to)719-728
Number of pages10
JournalNeurosurgery
Volume73
Issue number4
DOIs
StatePublished - Oct 2013
Externally publishedYes

Keywords

  • Glutamate
  • Haptoglobin
  • S-4-CPG
  • SAH
  • Subarachnoid
  • Vasospasm

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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