Glycine site antagonist attenuates infarct size in experimental focal ischemia. Postmortem and diffusion mapping studies.
OBJECTIVE
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.
Takano
K
K
Department of Neurology, Medical Center of Central Massachusetts 01605-2982, USA.
Tatlisumak
T
T
Formato
J E
JE
Carano
R A
RA
Bergmann
A G
AG
Pullan
L M
LM
Bare
T M
TM
Sotak
C H
CH
Fisher
M
M
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D004058:Diffusion; D008279:Magnetic Resonance Imaging; D014677:Pharmaceutical Vehicles; D011724:Pyridazines / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*
D014677:Pharmaceutical Vehicles; D011724:Pyridazines; D011804:Quinolines; D018009:Receptors, Glycine; C106383:ZD 9379