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 uncompetitive N-methyl-D-aspartate antagonist, on infarct size, extent of swelling 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 poly-L-lysine. The agent (MRZ 2/579) or vehicle (sodium chloride 0.9%) was administered i.v. immediately after suture removal following a 2-h period of MCAo. 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 followed by infusion of 6 mg/kg/h over 6 h). The neurological status was evaluated during occlusion (at 60 min) and daily for 3 days after MCAo. Brains were then perfusion-fixed, and infarct volumes and brain swelling were determined. 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<0.004) and 72 h after MCAo (5.2+/-0.6 and 8.4+/-0.5, respectively; P<0.001). Treatment 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 volume (24.8+/-11.2 and 70.0+/-18.0 mm(3), respectively; P<0.04) and subcortical infarction (21.2+/-4.1 and 49. 6+/-4.5 mm(3), respectively; P<0.0002). Brain 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 reperfusion, confers neuroprotective effects on infarct volume, brain swelling, and neurological score compared to the vehicle group.
Liu
Y
Y
Cerebral Vascular Disease Research Center, Department of Neurology (D4-5), University of Miami School of Medicine, Miami, FL, USA.
Belayev
L
L
Zhao
W
W
Busto
R
R
Ginsberg
M D
MD
D000818:Animals; D001929:Brain Edema / Q000188:drug therapy* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy; D002540:Cerebral Cortex / Q000098:blood supply / Q000473:pathology; D003517:Cyclopentanes / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists; D007091:Image Processing, Computer-Assisted; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D017072:Neostriatum / Q000098:blood supply / Q000473:pathology; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D003517:Cyclopentanes; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D016202:N-Methylaspartate; C114144:neramexane