MRZ 2/579, a novel uncompetitive N-methyl-D-aspartate antagonist, reduces infarct volume and brain swelling and improves neurological deficit after focal cerebral ischemia in rats

The purpose of this study was to evaluate the effects of MRZ 2/579, an unco mpetitive N-methyl-D-aspartate antagonist, on infarct size, extent of swell ing and neurological deficit in a model of transient middle cerebral artery occlusion in rats. Physiologically controlled Sprague-Dawley rats received 2 h MCAo by retrograde insertion of an intraluminal suture coated with pol y-L-lysine. The agent (MRZ 2/579) or vehicle (sodium chloride 0.9%) was adm inistered i.v. immediately after suture removal following a 2-h period of M CAo. Two experimental groups were studied: group A was treated by vehicle ( bolus infusion:1 ml/kg for 10 min followed by infusion of 6 ml/kg/h over 6 h). Group B was treated by MRZ 2/579 (bolus infusion:10 mg/kg for 10 min fo llowed by infusion of 6 mg/kg/h over 6 h). The neurological status was eval uated during occlusion (at 60 min) and daily for 3 days after MCAo. Brains were then perfusion-fixed, and infarct volumes and brain swelling were dete rmined. MRZ 2/579 significantly improved the neurological score compared to vehicle-treated rats at 48 h (6.2+/-0.6 and 8.7+/-0.5, respectively; P<0.0 04) and 72 h after MCAo (5.2+/-0.6 and 8.4+/-0.5, respectively; P<0.001). T reatment with MRZ 2/579 also significantly reduced total infarct volume (29 .3+/-11.1 and 83.2+/-16.5 mm(3), respectively; P<0.01), cortical infarct vo lume (24.8+/-11.2 and 70.0+/-18.0 mm(3), respectively; P<0.04) and subcorti cal infarction (21.2+/-4.1 and 49.6+/-4.5 mm(3) respectively; P<0.0002). Br ain swelling was also markedly reduced compared with vehicle-treated rats ( 4.7+/-1.3 and 10.8+/-2.1%, respectively; P<0.02). These results demonstrate that treatment with MRZ 2/579, when administered promptly after reperfusio n, confers neuroprotective effects on infarct volume, brain swelling, and n eurological score compared to the vehicle group. (C) 2000 Elsevier Science B.V. All rights reserved.