Systemic L-Citrulline Prevents Cerebral Vasospasm in Haptoglobin 2-2 Transgenic Mice After Subarachnoid Hemorrhage

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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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