Reduction of glutamate release and protection against ischemic brain damage by BW 1003C87.
BW 1003C87, 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonic acid, has been tested for its in vitro and in vivo effects on glutamate release in rat brain tissue, and for its cerebro-protective action in two rodent models of cerebral ischemia. In rat brain slices the release of glutamate evoked by veratrine is inhibited by BW 1003C87 (IC50 = 1.6 microM). In anaesthetised rats with microdialysis probes implanted in the dorsal hippocampus the increase in extracellular glutamate evoked by veratrine is markedly reduced by co-infusion of BW 1003C87, 100 microM. In anaesthetised rats with microdialysis probes implanted in the cortex and the caudate nucleus ipsilateral to a middle cerebral artery (MCA) occlusion the increase in dialysate glutamate concentration seen in the first 2 h following MCA occlusion is markedly attenuated by the prior administration of BW 1003C87, 20 mg/kg i.v. In rats subjected to 10 min of bilateral common carotid artery occlusion the loss of CA1 pyramidal neurons (assessed 7 days later) is reduced by administration of BW 1003C87 (20 mg/kg i.v., at the time of ischemia and 4 h later). The volume of cortex showing infarction 72 h after unilateral MCA occlusion is reduced by treatment with BW 1003C87 (20 mg/kg, i.v., beginning 5 min after occlusion). Inhibition of glutamate release may provide a therapeutic approach in cerebral ischemia as well as in epilepsy.
Meldrum
B S
BS
Department of Neurology, Institute of Psychiatry, London UK.
Swan
J H
JH
Leach
M J
MJ
Millan
M H
MH
Gwinn
R
R
Kadota
K
K
Graham
S H
SH
Chen
J
J
Simon
R P
RP
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D002536:Cerebral Arteries / Q000502:physiology; D005971:Glutamates / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013654:Taurine / Q000378:metabolism; D014702:Veratrine / Q000494:pharmacology
D005971:Glutamates; D011743:Pyrimidines; D005973:Glutamine; C078265:5-(2,3,5-trichlorophenyl)pyrimidine-2,4-diamine ethane sulfonate; D013654:Taurine; D001224:Aspartic Acid; D014702:Veratrine