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.
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).


CONCLUSIONS
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.
Dempsey
R J
RJ
Department of Neurological Surgery, University of Wisconsin, Madison, USA.
Başkaya
M K
MK
Doğan
A
A
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy*; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D008297:Male; D010880:Piperidines / Q000627:therapeutic use*; D011073:Polyamines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil