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

Abstract

Background Vasospasm contributes to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Glutamate concentrations increase after aSAH and correlate with vasospasm in experimental SAH. The Hp2-2 genotype is associated with higher risk of vasospasm after SAH. We tested the efficacy of S-4-CPG, a metabotropic glutamate receptor inhibitor, for treatment of vasospasm after SAH in Hp2-2 and Hp1-1 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 (BBB) in vivo. Toxicity was assessed by administering escalating 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 (p-VASP), but glutamate treatment in the presence of S-4-CPG maintains p-VASP. S-4-CPG crosses the BBB 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 towards 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.

Behavioural Effects of Using Sulfasalazine to Inhibit Glutamate Released by Cancer Cells: A Novel target for Cancer-Induced Depression

“…SSZ is a clinically useful and well-tolerated system x c − inhibitor52. Valuable insight may be derived from further investigation of more specific system x c − inhibitors, such as S-4-carboxy-phenylglycine (S-4-CPG)53. However, the pharmacokinetics of orally administered S-4-CPG has not been described, and this model would likely require daily intraperitoneal injections or surgically implanted osmotic pumps.…”

Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review

“…Additionally, glutamate toxicity has been shown to play an important role in the neuroinflammatory cascade and injury expansion following SAH [ 115 ]. Glutamate modulation was shown to reduce signs of CV in both human endothelial cells and in a mouse model of SAH [ 116 ].…”

Precision medicine of aneurysmal subarachnoid hemorrhage, vasospasm and delayed cerebral ischemia

“…Furthermore, Leclerc et al found that patients with the Hp 2-2 phenotype were significantly more likely to have moderate, severe, or global CV, trended toward poorer outcomes as measured by mRS and GOS, and had increased incidence of mortality [81]. Several novel therapies have been effective in preventing vasospasm in mice with Hp 2-2 phenotype, including glutamate receptor antagonists [82], systemic L-citrulline [83], glutathione peroxidase mimetic [84], and controlled nitric oxide delivery [85]. Human clinical trials addressing targeted treatment of those with Hp 2-2 phenotype with novel therapies are lacking.…”

“…Rosaglitazone, an anti-hyperglycemic thiazolidinedione, was shown to lower CSF glutamate levels and reduce mortality, CV, and neurological deficits in an experimental rat model [123]. As discussed above, treatment of haptoglobin 2-2 phenotype mice with a glutamate receptor antagonist resulted in prevention of CV [82]. …”