Background and Purpose The competitive N-methyl-D-aspartate antagonist
MDL-100,453 was used to determine whether a neuroprotective effect is
demonstrable when the drug is administered beginning 30 minutes after
the initiation of focal ischemia and whether the effect is related to
blood levels of the drug. Methods Forty-eight Sprague-Dawley rats wer
e randomly assigned to one of four intravenous treatment categories: a
bolus of 100 mg/kg MDL-100,453 followed by a saline infusion for 24 h
ours, isotonic saline as a bolus and 100 mg/kg per 24 hours of MDL-100
,453 as an infusion over 24 hours, active drug in the bolus and 24-hou
r infusion, and control treatment of an isotonic saline bolus and infu
sion. Focal cerebral ischemia was induced by the intraluminal suture,
middle cerebral artery occlusion method. The drug infusion was accompl
ished by an osmotic minipump implanted under,the skin and attached to
the jugular vein, which delivered drug or vehicle over a period of 24
hours. Infarct volume was calculated using 2,3,5-triphenyltetrazolium
chloride staining after 24 hours of middle cerebral artery occlusion.
Results Infarct volume of animals that received the MDL-100,453 bolus
injection followed by MDL-100,453 infusion was significantly smaller t
han that of controls (P<.01). A significant effect of infusion on the
reduction of extent of infarct size was also demonstrated (P=.015). Mo
reover, a statistically significant inverse correlation was demonstrat
ed between the infarct volume and blood levels of MDL-100,453 at 60 mi
nutes and 120 minutes after injection (r=-.33 and r=-.49, respectively
). Conclusions We demonstrated a significant neuroprotective effect of
MDL-100,453 when treatment was initiated 30 minutes after ischemia be
gan and was maintained for 24 hours.