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 Dogan

Research output: Contribution to journalArticle

73 Citations (Scopus)

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 - 2000
Externally publishedYes

Fingerprint

Brain Edema
Polyamines
N-Methyl-D-Aspartate Receptors
Blood-Brain Barrier
Wounds and Injuries
Evans Blue
Brain
ifenprodil
Traumatic Brain Injury
Brain Injuries
Sprague Dawley Rats
Calcium
Amino Acids
Equipment and Supplies
Water

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

@article{08ebbb62e2e641e9a5581231981aca10,
title = "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",
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.",
keywords = "Blood-brain barrier, Brain edema, Ifenprodil, NMDA receptors, Polyamines, Traumatic brain injury",
author = "Dempsey, {Robert J.} and Bakaya, {Mustafa K.} and Aclan Dogan",
year = "2000",
doi = "10.1097/00006123-200008000-00024",
language = "English (US)",
volume = "47",
pages = "399--406",
journal = "Neurosurgery",
issn = "0148-396X",
publisher = "Lippincott Williams and Wilkins",
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}

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T1 - 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

AU - Dempsey, Robert J.

AU - Bakaya, Mustafa K.

AU - Dogan, Aclan

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

KW - Blood-brain barrier

KW - Brain edema

KW - Ifenprodil

KW - NMDA receptors

KW - Polyamines

KW - Traumatic brain injury

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