A GLYCINE SITE ANTAGONIST, ZD9379, REDUCES NUMBER OF SPREADING DEPRESSIONS AND INFARCT SIZE IN RATS WITH PERMANENT MIDDLE CEREBRAL-ARTERY OCCLUSION

Background and Purpose-Spreading depressions (SDs) occur in experiment al focal ischemia and contribute to lesion evolution. N-Methyl-D-aspar tate (NMDA) antagonists inhibit SDs and reduce infarct size. The glyci ne site oil the NMDA receptor complex offers a therapeutic target for acute local ischemia, potentially devoid of many side effects associat ed with competitive and noncompetitive NMDA antagonists, We evaluated the effect of the glycine antagonist ZD9379 un SDs and brain infarctio n. Methods-Male Sprague-Dawley rats (n=18) weighing 290 to 340 g under going permanent middle cerebral artery occlusion (MCAO) were randomly and blindly assigned to receive drug or placebo: group 1 (pre-MCAO tre atment 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 bef ore 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 infusi on for 4 hours. and group 3 (control group; n=6), vehicle for hours be ginning 3(, minutes before MCAO. SDs were monitored electrophysiologic ally for 4.5 hours after MCAO by continuous recording of cortical DC p otentials and electrocorticogram. Infarct volume was measured 24 hours after MCAO by 2,3,5-triphenyltetrazolium chloride staining, Results-C orrected infarct volume was 90+/-72 mm(3) (mean+/-standard deviation) in group 1, 105+/-46 mm(3) in group 2, and 226+/-40 mm(3) 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 anim als (n=18) were analyzed, infarct volumes and the number of SDs were s ignificantly correlated (r=.68, P=.002). Conclusions-This study demons trated that ZD9379 initiated before or after MCAO significantly reduce d the number of SDs and infarct volume ill a permanent focal ischemia model, implying that ZD9379 is neuroprotective and its neuroprotective effect may be related to inhibiting ischemia-related SDs.