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 s hown io attenuate ischemic cell damage when administered after permane nt focal cerebral ischemia. The aim of the present study was to measur e the dose-response of cerebral infarcted Volume to the agent administ ered 30 min after permanent middle cerebral artery occlusion and to te st whether shore-ten infusion of this drug reduces ischemic cell damag e. Thirty-five Sprague-Dawley rats were randomly assigned to Li groups : low dose group, a bolus of 12.4 mg/kg MDL-100, 453 followed by infus ion of 31.7 mg/kg/h MDL-100,453; middle and high dose groups, bolus an d 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 bolu s 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 deli vered drug or saline over a period of 9 h, Infarct Volume was calculat ed using 2,3,5-triphenyltetrazolium chloride staining 24 h after MCAO. The infarct volumes were significantly reduced in both middle (46%) a nd high (52%) dose groups compared with the saline group (p < 0.05). N o reduction of infarct volume was found in the low dose group. A stati stically 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 significan tly reduces ischemic lesion volume at 24 h after onset of permanent fo cal cerebral ischemia.