GLYCINE SITE ANTAGONIST ATTENUATES INFARCT SIZE IN EXPERIMENTAL FOCALISCHEMIA - POSTMORTEM AND DIFFUSION MAPPING STUDIES

Background and Purpose The glycine site on the N-methyl-D-aspartate (N MDA) receptor complex offers a therapeutic target for acute focal isch emia, potentially devoid of most side effects associated with competit ive and noncompetitive NMDA antagonists. Methods A novel glycine recep tor antagonist, ZD9379, was studied in 70 Sprague-Dawley rats using th e suture occlusion model of permanent middle cerebral artery occlusion (MCAO). In the first experiment, 20 rats received an initial bolus of vehicle or 10 mg/kg ZD9379 (n=10 in each group) 30 minutes after MCAO , followed by a continuous infusion of the same dose per hour for 4 ho urs. Diffusion-weighted MRI with echo-planar acquisition was used to g enerate maps of the apparent diffusion coefficient (ADC) of water. In a second experiment, 50 rats were assigned to five groups: vehicle and 10, 5, 2.5, and 1 mg/kg ZD9379 (n=10 in each group) with the same dos ing protocol but no imaging. In both experiments, infarct volume was d etermined by 2,3,5-triphenyltetrazolium chloride staining. Results In the first experiment, before therapy was begun, there was no significa nt difference in ADC-derived ischemic lesion volume between the two gr oups. Over time, the 10-mg/kg ZD9379-treated rats had a significant de layed regional recovery of reduced ADC values in the peripheral pariet al cortex (P=.0156). Postmortem corrected infarct volume at 24 hours a fter MCAO was significantly smaller in the group treated with 10 mg/kg ZD9379 than in the vehicle group (119.2+/-52.2 versus 211.2+/-50.0 mm (3) [mean+/-SD]; P=.0008; a reduction of 43.6%). In the second experim ent, postmortem corrected infarct volumes in rats receiving 10, 5, and 2.5 mg/kg ZD9379 were significantly smaller than in those receiving v ehicle, a reduction of 42.6%, 51.4%, and 42.9%, respectively (P=.0001) . Conclusions This study demonstrates that 2.5- to 10-mg/kg doses of Z D9379 initiated 30 minutes after MCAO significantly reduced infarct si ze. Diffusion mapping disclosed a delayed treatment effect of this gly cine antagonist in focal ischemia, confirmed by the postmortem study.