From the Department of Neurology, Helsinki University Central Hospital
(Finland) (T.T.); Department of Neurology, Medical Center of Central
Massachusetts–Memorial and the University of Massachusetts Medical
School, Worcester, Mass (T.T., K.T., M.F.); and Department of Biomedical
Engineering, Worcester Polytechnic Institute (Mass) (M.R.M.).
Background and
Purpose—Spreading depressions (SDs) occur in experimental focal
ischemia and contribute to lesion evolution.
N-Methyl-D-aspartate (NMDA)
antagonists inhibit SDs and reduce infarct size. The
glycine site on the NMDA receptor complex offers a therapeutic target
for acute focal ischemia, potentially devoid of many side
effects associated with competitive and noncompetitive NMDA
antagonists. We evaluated the effect of the glycine
antagonist ZD9379 on SDs and brain infarction.
Methods—Male Sprague-Dawley rats (n=18) weighing 290 to 340
g undergoing permanent middle cerebral artery occlusion (MCAO) were
randomly and blindly assigned to receive drug or placebo: group 1
(pre-MCAO treatment group; n=5), a 5-mg/kg bolus of ZD9379 over 5
minutes followed by 5 mg/kg per hour drug infusion for 4 hours
beginning 30 minutes before MCAO; group 2 (post-MCAO treatment group;
n=7), a 5-mg/kg bolus of ZD9379 30 minutes after MCAO followed by 5
mg/kg per hour drug infusion for 4 hours; and group 3 (control group;
n=6), vehicle for 5 hours beginning 30 minutes before MCAO. SDs were
monitored electrophysiologically for 4.5
hours after MCAO by continuous recording of cortical DC
potentials and electrocorticogram. Infarct volume was measured 24 hours
after MCAO by 2,3,5-triphenyltetrazolium
chloride staining.
Results—Corrected infarct volume was 90±72 mm3
(mean±standard deviation) in group 1, 105±46 mm3 in
group 2, and 226±40 mm3 in group 3
(P<.001). The corresponding numbers of SDs in the three
groups were 8.2±5.8, 8.1±2.5, and 16.0±5.1, respectively
(P<.01). When all animals (n=18) were analyzed,
infarct volumes and the number of SDs were significantly correlated
(r=.68, P=.002).
Conclusions—This study demonstrated that ZD9379 initiated before
or after MCAO significantly reduced the number of SDs and infarct
volume in a permanent focal ischemia model, implying that
ZD9379 is neuroprotective and its neuroprotective effect may be related
to inhibiting ischemia-related SDs.
Department
of Neurology,
University of Miami School of Medicine,
Miami, Florida
© 1998 American Heart Association, Inc.
Original Contributions
A Glycine Site Antagonist, ZD9379, Reduces Number of Spreading Depressions and Infarct Size in Rats With Permanent Middle Cerebral Artery Occlusion
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