A novel inhibitor of glutamate release reduces excitotoxic injury in vitro.
Excessive release of glutamate has been implicated in the pathogenesis of excitotoxic neurologic disorders, such as stroke. BW 1003C87, an inhibitor of glutamate release and a putative Na+ channel antagonist, reduced veratridine-stimulated, tetrodotoxin- and dizocilpine-sensitive toxicity (measured by lactate dehydrogenase efflux) in neuron-enriched cortical cultures (IC50 = 5 microM). In contrast, BW 1003C87 (300 microM) had no effect on toxicity induced by direct application of 1 mM glutamate or 1 mM N-methyl-D-aspartate, or by depolarization with 50 mM KCl. Glutamate release inhibitors such as BW 1003C87 may provide a novel approach to protection from excitotoxicity.
Department of Neurology, University of California, San Francisco 94110.
H S
HS
Lustig
K L
KL
von Brauchitsch
J
J
Chan
D A
DA
Greenberg
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism / Q000633:toxicity*; D018698:Glutamic Acid; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D011189:Potassium Chloride / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley / Q000196:embryology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000037:antagonists & inhibitors / Q000633:toxicity
D005971:Glutamates; D009498:Neurotoxins; D011743:Pyrimidines; D015222:Sodium Channels; C078265:5-(2,3,5-trichlorophenyl)pyrimidine-2,4-diamine ethane sulfonate; D018698:Glutamic Acid; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D011189:Potassium Chloride; D016291:Dizocilpine Maleate; D014701:Veratridine