A Glutamate Receptor Antagonist, S-4-Carboxyphenylglycine (S-4-CPG), Inhibits Vasospasm After Subarachnoid Hemorrhage in Haptoglobin 2 to 2 Mice

作者：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^*

来源：Neurosurgery, 2013, 73(4): 719-728.

DOI：10.1227/NEU.0000000000000080

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

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. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2013-10