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 journalArticle

12 Citations (Scopus)

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 1 2013
Externally publishedYes

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Excitatory Amino Acid Antagonists
Haptoglobins
Subarachnoid Hemorrhage
Glutamic Acid
Phosphorylation
Animal Behavior
Basilar Artery
Poisons
Blood-Brain Barrier
4-carboxyphenylglycine
Metabotropic Glutamate Receptors
Therapeutics
Brain Ischemia

Keywords

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

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

A glutamate receptor antagonist, S-4-carboxyphenylglycine (S-4-CPG), inhibits vasospasm after subarachnoid hemorrhage in haptoglobin 2 to 2 mice. / Garzon-Muvdi, Tomas; Pradilla, Gustavo; Ruzevick, Jacob J.; Bender, Matthew; Edwards, Lindsay; Grossman, Rachel; Zhao, Ming; Rudek, Michelle A.; Riggins, Gregory; Levy, Andrew; Tamargo, Rafael J.

In: Neurosurgery, Vol. 73, No. 4, 01.10.2013, p. 719-728.

Research output: Contribution to journalArticle

Garzon-Muvdi, T, Pradilla, G, Ruzevick, JJ, Bender, M, Edwards, L, Grossman, R, Zhao, M, Rudek, MA, Riggins, G, Levy, A & Tamargo, RJ 2013, 'A glutamate receptor antagonist, S-4-carboxyphenylglycine (S-4-CPG), inhibits vasospasm after subarachnoid hemorrhage in haptoglobin 2 to 2 mice', Neurosurgery, vol. 73, no. 4, pp. 719-728. https://doi.org/10.1227/NEU.0000000000000080
Garzon-Muvdi, Tomas ; Pradilla, Gustavo ; Ruzevick, Jacob J. ; Bender, Matthew ; Edwards, Lindsay ; Grossman, Rachel ; Zhao, Ming ; Rudek, Michelle A. ; Riggins, Gregory ; Levy, Andrew ; Tamargo, Rafael J. / A glutamate receptor antagonist, S-4-carboxyphenylglycine (S-4-CPG), inhibits vasospasm after subarachnoid hemorrhage in haptoglobin 2 to 2 mice. In: Neurosurgery. 2013 ; Vol. 73, No. 4. pp. 719-728.
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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.",
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T1 - A glutamate receptor antagonist, S-4-carboxyphenylglycine (S-4-CPG), inhibits vasospasm after subarachnoid hemorrhage in haptoglobin 2 to 2 mice

AU - Garzon-Muvdi, Tomas

AU - Pradilla, Gustavo

AU - Ruzevick, Jacob J.

AU - Bender, Matthew

AU - Edwards, Lindsay

AU - Grossman, Rachel

AU - Zhao, Ming

AU - Rudek, Michelle A.

AU - Riggins, Gregory

AU - Levy, Andrew

AU - Tamargo, Rafael J.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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.

AB - 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.

KW - Glutamate

KW - Haptoglobin

KW - S-4-CPG

KW - SAH

KW - Subarachnoid

KW - Vasospasm

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