COMPETITIVE N-METHYL-D-ASPARTATE RECEPTOR BLOCKADE REDUCES BRAIN INJURY FOLLOWING TRANSIENT FOCAL ISCHEMIA IN CATS

Background and Purpose We tested the hypothesis that administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist NPC 1 7742 [2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid]) during transient focal ischemia affects early postischemic brain injury. Meth ods Halothane-anesthetized cats underwent 1 hour of left middle cerebr al artery occlusion plus 4 hours of reperfusion. Control cats received saline (n=7). Experimental cats were treated with NPC 17742 at a dose of 5 mg/kg IV from 45 minutes of ischemia to 15 minutes of reperfusio n and 2.5 mg/kg per hour for 4 hours of reperfusion (NPC-5; n=7) or 50 mg/kg from 45 minutes of ischemia to 15 minutes of reperfusion and 25 mg/kg per hour for 4 hours of reperfusion (NPC-50; n=5). Results Micr osphere-determined blood how to the ipsilateral inferior temporal cort ex and caudate nucleus decreased to the same extent during ischemia an d recovered to the same extent during reperfusion in the three groups. Triphenyltetrazolium-determined injury volume of ipsilateral cerebral hemisphere (saline, 24+/-8%; NPC-5, 4+/-2%; NPC-50, 5+/-2% of hemisph ere; mean+/-SE) and caudate nucleus (saline, 72+/-6%; NPC-5, 37+/-10%s NPC-50, 26+/-4%) was less in cats treated with both doses of drug com pared with cats treated with saline. Recovery of somatosensory evoked potential amplitude was incomplete and similar in all groups (saline, 36+/-14%; NPC-5, 58+/-8%; NPC-50, 51+/-15% of baseline). Conclusions T hese data indicate that activation of NMDA receptors plays an importan t role in the mechanism of acute injury in both cortex and caudate aft er 1 hour of transient focal ischemia in the cat. Because NPC 17742 af forded protection when administered at the end of ischemia and during reperfusion, NMDA receptor activation during reperfusion may contribut e to the progression of injury in ischemic border regions.