Administration of a competitive NMDA antagonist MDL-100,453 reduces infarct size after permanent middle cerebral artery occlusion in rat.
The competitive N-methyl-D-aspartate antagonist MDL-100,453 has been shown to attenuate ischemic cell damage when administered after permanent focal cerebral ischemia. The aim of the present study was to measure the dose-response of cerebral infarcted volume to the agent administered 30 min after permanent middle cerebral artery occlusion and to test whether short-term infusion of this drug reduces ischemic cell damage. Thirty-five Sprague-Dawley rats were randomly assigned to 4 groups: low dose group, a bolus of 12.4 mg/kg MDL-100,453 followed by infusion of 31.7 mg/kg/h MDL-100,453; middle and high dose groups, bolus and infusion doses increased to 24.8 mg/kg, 63.3 mg/kg/h and 49.6 mg/kg, 126.7 mg/kg/h, respectively; and control group, saline used for bolus and infusion. Middle cerebral artery occlusion (MCAO) was induced by insertion of intraluminal suture. The infusion was accomplished by a microprocessor controlled pump connected to a jugular vein, which delivered drug or saline over a period of 9 h. Infarct volume was calculated using 2,3,5-triphenyltetrazolium chloride staining 24 h after MCAO. The infarct volumes were significantly reduced in both middle (46%) and high (52%) dose groups compared with the saline group (p < 0.05). No reduction of infarct volume was found in the low dose group. A statistically significant (p < 0.05), but poor inverse correlation existed between the average blood level of MDL-100,453 and infarct volume. We demonstrated that a short-term (9 h) intravenous administration of an appropriate dose of MDL-100,453 beginning 30 min after MCAO significantly reduces ischemic lesion volume at 24 h after onset of permanent focal cerebral ischemia.
Jiang
N
N
Department of Neurology, Henry Ford Health Science Center, Detroit, MI 482202, USA.
Zhang
R L
RL
Baron
B M
BM
Chopp
M
M
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy*; D002545:Brain Ischemia / Q000188:drug therapy*; D002536:Cerebral Arteries; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C066280:4-oxo-5-phosphononorvaline; D014633:Valine