METHODS: RESULTS: In the in vitro studies,
BW619C89 inhibited
veratrine- (but not
potassium-) evoked release of both endogenous
glutamate and
aspartate from rat cerebral cortex slices with IC50 values of approximately 5 microM.
BW619C89 was approximately 10-fold less potent to inhibit
veratrine-evoked 3H-gamma-aminobutyric
acid release (IC50 = 51 microM), fourfold less potent to inhibit 3H-acetylcholine release (IC50 = 21 microM), and
at 10 microM had only weak activity at
excitatory amino acid (N-methyl-D-aspartate, kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding sites. When administered intravenously to Fischer 344 rats 5 minutes after permanent
middle cerebral artery occlusion,
BW619C89 produced marked reductions of both total (cortex and basal ganglia) and cortical
infarct volumes. Cortical
infarct size was reduced by 20% at a dose of
BW619C89 of 5 mg/kg (n = 6, not significant); 43%
at 10 mg/kg (n = 8, P < .01); 59% at 20 mg/kg (n = 8, P < .001); 61% at 30 mg/kg (n = 8, P < .001), and 53% at 40 mg/kg (n = 8, P < .001).
BW619C89 at doses of 20 and 30 mg/kg also significantly reduced noncortical (basal ganglia)
infarct volumes, demonstrating that a proportion of this tissue also appears to be salvageable. Behavioral effects observed were dose related, generally minor, and at doses of 20 mg/kg IV and above consisted of body
tremor and mild
ataxia lasting approximately 2 hours.
CONCLUSIONS: