Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage.

Gustavo Pradilla, Tomas Garzon-Muvdi, Jacob J. Ruzevick, Matthew Bender, Lindsay Edwards, Eric N. Momin, Reid C. Thompson, Rafael J Tamargo

Research output: Contribution to journalArticle

Abstract

Nitric oxide (NO) depletion and periadventitial inflammation contribute to the pathogenesis of cerebral vasospasm. L-Citrulline increases L-arginine levels, thereby raising NO synthesis. Transgenic C57Bl6 mice with a haptoglobin (Hp) 2-2 genotype develop more severe vasospasm than wild-type (Hp 1-1) mice after subarachnoid hemorrhage (SAH). To evaluate the toxicity of systemic L-citrulline and its effect on basilar artery (BA) vasospasm, neurobehavioral scores, and inducible NO synthase (iNOS)/endothelial NO synthase (eNOS) expression after SAH in Hp 2-2 mice. The Hp 2-2 genotypes were confirmed by reverse-transcriptase polymerase chain reaction. Toxicity was assessed with escalating L-citrulline doses. To test efficacy, Hp 1-1 and Hp 2-2 mice (n = 64) were divided into 4 groups (n = 32 per genotype): sham surgery (n = 8), SAH with no treatment (n = 8), SAH + vehicle (n = 8), and SAH + L-citrulline (200 mg/kg IP every 8 hours; n = 8). Post-SAH neurobehavioral scores were recorded at 24 hours; animals were perfused; and BAs were processed for analysis. Expression of iNOS and eNOS was determined by reverse-transcriptase polymerase chain reaction. The administration of L-citrulline resulted in higher BA lumen patencies in both genotypes (Hp 1-1: SAH + vehicle, 77.8 ± 3.2% vs SAH + L-citrulline, 91.8 ± 5.9% [mean ± SEM]; P < .05; Hp 2-2: SAH + vehicle, 67.1 ± 2.0% vs SAH + L-citrulline, 86.9 ± 2.2%; P < .001). Neurobehavioral scores were higher in Hp 2-2 mice treated with L-citrulline (SAH + vehicle, 1.2 ± 0.2 vs SAH + L-citrulline, 2.4 ± 0.2; P < .01). Expression of iNOS and eNOS increased in Hp 2-2 mice after L-citrulline treatment, but limited sample sizes prevented further statistical analysis. L-Citrulline was not toxic even at the highest dose. L-Citrulline is safe; increases BA patency, neurobehavioral scores, and NOS expression in Hp 2-2 mice after SAH; and is a potential agent for treatment of vasospasm after SAH.

Original languageEnglish (US)
JournalNeurosurgery
Volume70
Issue number3
StatePublished - 2012
Externally publishedYes

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Intracranial Vasospasm
Citrulline
Haptoglobins
Subarachnoid Hemorrhage
Transgenic Mice
Nitric Oxide Synthase
Basilar Artery
Genotype
Reverse Transcriptase Polymerase Chain Reaction
Nitric Oxide
Nitric Oxide Synthase Type III
Poisons
Nitric Oxide Synthase Type II
Sample Size

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Pradilla, G., Garzon-Muvdi, T., Ruzevick, J. J., Bender, M., Edwards, L., Momin, E. N., ... Tamargo, R. J. (2012). Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage. Neurosurgery, 70(3).

Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage. / Pradilla, Gustavo; Garzon-Muvdi, Tomas; Ruzevick, Jacob J.; Bender, Matthew; Edwards, Lindsay; Momin, Eric N.; Thompson, Reid C.; Tamargo, Rafael J.

In: Neurosurgery, Vol. 70, No. 3, 2012.

Research output: Contribution to journalArticle

Pradilla, G, Garzon-Muvdi, T, Ruzevick, JJ, Bender, M, Edwards, L, Momin, EN, Thompson, RC & Tamargo, RJ 2012, 'Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage.', Neurosurgery, vol. 70, no. 3.
Pradilla G, Garzon-Muvdi T, Ruzevick JJ, Bender M, Edwards L, Momin EN et al. Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage. Neurosurgery. 2012;70(3).
Pradilla, Gustavo ; Garzon-Muvdi, Tomas ; Ruzevick, Jacob J. ; Bender, Matthew ; Edwards, Lindsay ; Momin, Eric N. ; Thompson, Reid C. ; Tamargo, Rafael J. / Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage. In: Neurosurgery. 2012 ; Vol. 70, No. 3.
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title = "Systemic L-citrulline prevents cerebral vasospasm in haptoglobin 2-2 transgenic mice after subarachnoid hemorrhage.",
abstract = "Nitric oxide (NO) depletion and periadventitial inflammation contribute to the pathogenesis of cerebral vasospasm. L-Citrulline increases L-arginine levels, thereby raising NO synthesis. Transgenic C57Bl6 mice with a haptoglobin (Hp) 2-2 genotype develop more severe vasospasm than wild-type (Hp 1-1) mice after subarachnoid hemorrhage (SAH). To evaluate the toxicity of systemic L-citrulline and its effect on basilar artery (BA) vasospasm, neurobehavioral scores, and inducible NO synthase (iNOS)/endothelial NO synthase (eNOS) expression after SAH in Hp 2-2 mice. The Hp 2-2 genotypes were confirmed by reverse-transcriptase polymerase chain reaction. Toxicity was assessed with escalating L-citrulline doses. To test efficacy, Hp 1-1 and Hp 2-2 mice (n = 64) were divided into 4 groups (n = 32 per genotype): sham surgery (n = 8), SAH with no treatment (n = 8), SAH + vehicle (n = 8), and SAH + L-citrulline (200 mg/kg IP every 8 hours; n = 8). Post-SAH neurobehavioral scores were recorded at 24 hours; animals were perfused; and BAs were processed for analysis. Expression of iNOS and eNOS was determined by reverse-transcriptase polymerase chain reaction. The administration of L-citrulline resulted in higher BA lumen patencies in both genotypes (Hp 1-1: SAH + vehicle, 77.8 ± 3.2{\%} vs SAH + L-citrulline, 91.8 ± 5.9{\%} [mean ± SEM]; P < .05; Hp 2-2: SAH + vehicle, 67.1 ± 2.0{\%} vs SAH + L-citrulline, 86.9 ± 2.2{\%}; P < .001). Neurobehavioral scores were higher in Hp 2-2 mice treated with L-citrulline (SAH + vehicle, 1.2 ± 0.2 vs SAH + L-citrulline, 2.4 ± 0.2; P < .01). Expression of iNOS and eNOS increased in Hp 2-2 mice after L-citrulline treatment, but limited sample sizes prevented further statistical analysis. L-Citrulline was not toxic even at the highest dose. L-Citrulline is safe; increases BA patency, neurobehavioral scores, and NOS expression in Hp 2-2 mice after SAH; and is a potential agent for treatment of vasospasm after SAH.",
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