Takano K, Tatlisumak T, Formato J E, Carano R A, Bergmann A G, Pullan L M, Bare T M, Sotak C H, Fisher M
Department of Neurology, Medical Center of Central Massachusetts 01605-2982, USA.
Stroke. 1997 Jun;28(6):1255-62; discussion 1263. doi: 10.1161/01.str.28.6.1255.
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.
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.
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).
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.
N-甲基-D-天冬氨酸（NMDA）受体复合物上的甘氨酸位点为急性局灶性缺血提供了一个治疗靶点，可能没有与竞争性和非竞争性NMDA拮抗剂相关的大多数副作用。
使用永久性大脑中动脉闭塞（MCAO）的缝线闭塞模型，在70只Sprague-Dawley大鼠中研究了一种新型甘氨酸受体拮抗剂ZD9379。在第一个实验中，20只大鼠在MCAO后30分钟接受初始剂量的赋形剂或10mg/kg ZD9379（每组n = 10），随后每小时持续输注相同剂量，共4小时。采用回波平面采集的扩散加权MRI生成水的表观扩散系数（ADC）图。在第二个实验中，50只大鼠被分为五组：赋形剂组以及10、5、2.5和1mg/kg ZD9379组（每组n = 10），给药方案相同但不进行成像。在两个实验中，梗死体积均通过2,3,5-三苯基氯化四氮唑染色确定。
在第一个实验中，开始治疗前，两组之间ADC衍生的缺血性病变体积无显著差异。随着时间的推移，10mg/kg ZD9379治疗的大鼠在顶叶外周皮质中ADC值降低的区域恢复明显延迟（P = 0.0156）。MCAO后24小时的死后校正梗死体积在10mg/kg ZD9379治疗组中显著小于赋形剂组（119.2±52.2对211.2±50.0mm3[平均值±标准差]；P = 0.0008；减少43.6%）。在第二个实验中，接受10、5和2.5mg/kg ZD9379的大鼠的死后校正梗死体积显著小于接受赋形剂的大鼠，分别减少42.6%、51.4%和42.9%（P = 0.0001）。
本研究表明，MCAO后30分钟开始给予2.5至10mg/kg剂量的ZD9379可显著减小梗死面积。扩散图谱揭示了这种甘氨酸拮抗剂在局灶性缺血中的延迟治疗效果，死后研究证实了这一点。
