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 mg/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 microg/g versus 161.8 +/- 27 microg/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 mm3 versus 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.

• Authors: R J Dempsey, M K Başkaya, A Doğan
• Journal: Neurosurgery (Neurosurgery) Vol. 47 Issue 2 Pg. 399-404; discussion 404-6 (Aug 2000) ISSN: 0148-396X [Print] United States
• PMID: 10942013 (Publication Type: Journal Article)

Chemical References

• Excitatory Amino Acid Antagonists
• Piperidines
• Polyamines
• Receptors, N-Methyl-D-Aspartate
• ifenprodil

Topics

• Animals
• Blood-Brain Barrier (drug effects)
• Body Water (metabolism)
• Brain (metabolism)
• Brain Edema (drug therapy)
• Brain Injuries (drug therapy, pathology, physiopathology)
• Capillary Permeability (drug effects)
• Excitatory Amino Acid Antagonists (therapeutic use)
• Male
• Piperidines (therapeutic use)
• Polyamines (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, metabolism)