Prevention of experimental cerebral vasospasm by intracranial delivery of a nitric oxide donor from a controlled-release polymer: Toxicity and efficacy studies in rabbits and rats

Patrik Gabikian, Richard E. Clatterbuck, Charles G. Eberhart, Betty M. Tyler, Travis S. Tierney, Rafael J. Tamargo

Research output: Contribution to journalArticle

Abstract

Background and Purpose - A reduction in the local availability of nitric oxide (NO) may play a role in the etiology of chronic cerebral vasospasm after subarachnoid hemorrhage (SAH). We investigated the toxicity and efficacy of a locally delivered NO donor from a controlled-release polymer in preventing experimental cerebral vasospasm in rats and rabbits, respectively. Methods - Diethylenetriamine/NO (DETA/NO) was incorporated into controlled release ethylene-vinyl acetate (EVAc) polymers. Twenty-eight rats were used in a dose-escalation toxicity study to establish a maximally tolerated dose of DETA/NO-EVAc polymer. In the efficacy experiment, 20 rabbits were assigned to 4 experimental groups (n=5 per group): sham operation; SAH only; SAH+empty EVAc polymer; and SAH+DETA/NO-EVAc polymer. Treatment was initiated 30 minutes after blood deposition. Basilar artery lumen patency was assessed 72 hours after hemorrhage to evaluate the efficacy of DETA/NO in preventing cerebral vasospasm. Results - In the toxicity study, a dose of 3.4 mg/kg was identified as the LD20 (dose with 20% mortality during the study period) of this DETA/NO formulation. Brain histology revealed hemorrhage and ischemic changes at the implantation site associated with high concentrations of DETA/NO. In the efficacy study, treatment with DETA/NO-EVAc polymer resulted in a significant decrease in basilar artery vasospasm compared with no treatment (93.0±4.9% versus 71.4±11.9%; P=0.035) or compared with treatment with blank EVAc polymer (93.0±4.9% versus 73.2±6.4%; P=0.003). Conclusions - Local delivery of DETA/NO prevents vasospasm in the rabbit basilar artery. Local delivery of DETA/NO via polymers is a safe and effective strategy for preventing cerebral vasospasm after SAH in this model.

Original languageEnglish (US)
Pages (from-to)2681-2686
Number of pages6
JournalStroke
Volume33
Issue number11
DOIs
StatePublished - Nov 1 2002

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Keywords

  • Nitric oxide
  • Polymers
  • Rabbits
  • Rats
  • Subarachnoid hemorrhage
  • Vasospasm, intracranial

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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