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(Stroke. 1997;28:1255-1263.)
© 1997 American Heart Association, Inc.

Articles

Glycine Site Antagonist Attenuates Infarct Size in Experimental Focal Ischemia

Postmortem and Diffusion Mapping Studies

Kentaro Takano, MD, PhD; Turgut Tatlisumak, MD; James E. Formato, MS; Richard A. D. Carano, MS; Andreas G. Bergmann, MD; Linda M. Pullan, PhD; Thomas M. Bare, PhD; Christopher H. Sotak, PhD; Marc Fisher, MD

From the Department of Neurology, The Medical Center of Central Massachusetts and University of Massachusetts Medical School (K.T., T.T., A.G.B., M.F.), and the Department of Biomedical Engineering, Worcester Polytechnic Institute (J.E.F., R.A.D.C., C.H.S.), Worcester, Mass; Zeneca Pharmaceuticals, Wilmington, Del (L.M.P., T.M.B.); and the Department of Neurology, Helsinki University Central Hospital, Finland (T.T.).

Correspondence to Marc Fisher, MD, Memorial Health Care and University of Massachusetts Medical School, 119 Belmont St, Worcester, MA 01605-2982.

Background and Purpose The glycine site on the N-methyl-D-aspartate (NMDA) receptor complex offers a therapeutic target for acute focal ischemia, potentially devoid of most side effects associated with competitive and noncompetitive NMDA antagonists.

Methods A novel glycine receptor antagonist, ZD9379, was studied in 70 Sprague-Dawley rats using the 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 hours. Diffusion-weighted MRI with echo-planar acquisition was used to generate 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 dosing protocol but no imaging. In both experiments, infarct volume was determined by 2,3,5-triphenyltetrazolium chloride staining.

Results In the first experiment, before therapy was begun, there was no significant difference in ADC-derived ischemic lesion volume between the two groups. Over time, the 10-mg/kg ZD9379–treated rats had a significant delayed regional recovery of reduced ADC values in the peripheral parietal cortex (P=.0156). Postmortem corrected infarct volume at 24 hours after 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 mm³ [mean±SD]; P=.0008; a reduction of 43.6%). In the second experiment, postmortem corrected infarct volumes in rats receiving 10, 5, and 2.5 mg/kg ZD9379 were significantly smaller than in those receiving vehicle, 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 ZD9379 initiated 30 minutes after MCAO significantly reduced infarct size. Diffusion mapping disclosed a delayed treatment effect of this glycine antagonist in focal ischemia, confirmed by the postmortem study.

Key Words: ischemia • magnetic resonance imaging • middle cerebral artery occlusion • rats

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