Attenuation of brain edema, blood-brain barrier breakdown, and injury volume by ifenprodil, a polyamine-site N-methyl-D-aspartate receptor antagonist, after experimental traumatic brain injury in rats

Robert J. Dempsey, Mustafa K. Bakaya, Aclan Doǧan

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

OBJECTIVE: Traumatic brain injury (TBI) has been shown to induce a significant change in polyamine metabolism. Polyamines and polyamine-dependent calcium influx play an important role in mediating the effects of excitotoxic amino acids at the N-methyl-D-aspartate (NMDA) receptor site. We studied the effects of ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, on brain edema formation, blood-brain barrier breakdown, and volume of injury after TBI. METHODS: Experimental TBI was induced in Sprague-Dawley rats by a controlled cortical impact device, functioning at a velocity of 3 m/s to produce a 2-mm deformation. Ifenprodil or saline (10 ms/kg) was injected intraperitoneally immediately after the cortical impact injury and then every 90 minutes until 6 hours after TBI. Blood-brain barrier breakdown was evaluated quantitatively 6 hours after injury by fluorometric assay of Evans blue extravasation. Brain water content, an indicator of brain edema, was measured with the wet-dry method 24 hours after TBI. Injury volume was quantitated from the brain slices stained with 2% cresyl violet solution 7 days after TBI. RESULTS: Blood-brain barrier breakdown was significantly lower in the traumatic cortex of the ifenprodil-treated group than in the saline-treated group (84.4 ± 26.8 μg/g versus 161.8 ± 27 μg/g, respectively, P < 0.05). Brain edema was significantly reduced in the cortex of the ifenprodil-treated group relative to that in the saline-treated group (80.9 ± 0.5% versus 82.4 ± 0.6% respectively, P < 0.05). Ifenprodil treatment reduced injury volume significantly (14.9 ± 8.1 mm3versus 24.4 ± 6.7 mm3, P < 0.05). CONCLUSION: The polyamine-site NMDA receptor antagonist ifenprodil affords significant neuroprotection in a controlled cortical impact brain injury model and may hold promise for the discovery and treatment of the mechanism of delayed neurological deficits after TBI.

Original languageEnglish (US)
Pages (from-to)399-406
Number of pages8
JournalNeurosurgery
Volume47
Issue number2
DOIs
StatePublished - Dec 1 2000
Externally publishedYes

Keywords

  • Blood-brain barrier
  • Brain edema
  • Ifenprodil
  • NMDA receptors
  • Polyamines
  • Traumatic brain injury

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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