Limiting ischemic injury by inhibition of excitatory amino acid release.
Excitatory amino acids (EAAs) are important mediators of ischemic injury in stroke. N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to be very effective neuroprotective agents in animal models of stroke, but may have unacceptable toxicity for human use. An alternative approach is to inhibit the release of EAAs during stroke. BW1003C87 [5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine], a drug that inhibits veratrine-induced release of the EAA glutamate in vitro, was tested in a rat model of proximal middle cerebral artery (MCA) occlusion. BW1003C87 significantly decreased ischemia-induced glutamate release in brain when given either 5 min before or 15 min following permanent MCA occlusion. Pretreated and posttreated rats had smaller infarct volumes and preserved glucose metabolism in the ischemic cortex at 24 h after MCA occlusion. BW1003C87 did not induce heat shock protein in the cingulate or retrosplenial cortex, suggesting that it does not injure neurons in these regions as do NMDA antagonists. These results demonstrate that drugs that inhibit glutamate release in ischemia may be nontoxic and show promise for the treatment of stroke.
Graham
S H
SH
Department of Neurology, University of California, San Francisco.
Chen
J
J
Sharp
F R
FR
Simon
R P
RP
D000596:Amino Acids / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D005947:Glucose / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006360:Heat-Shock Proteins / Q000032:analysis; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000596:Amino Acids; D005971:Glutamates; D006360:Heat-Shock Proteins; D011743:Pyrimidines; C078265:5-(2,3,5-trichlorophenyl)pyrimidine-2,4-diamine ethane sulfonate; D018698:Glutamic Acid; D005947:Glucose