POSTISCHEMIC THERAPY WITH MK-801 (DIZOCILPINE) IN A PRIMATE MODEL OF TRANSIENT FOCAL BRAIN ISCHEMIA

The purpose of this study was to develop a primate model for assessing EEG, behavior and histology, and to test the effect of NMDA receptor blockade in transient focal ischemia. Squirrel monkeys (Saimiri sciure us) under halothane anesthesia were subjected to 110 min of transient focal ischemia (n = 15) by temporary clip occlusion of the MCA. An eig ht-lead EEG was recorded. Neurobehavioral testing was done in a subgro up of animals (n = 6). Brain temperature (37.5 degrees C) was monitore d and controlled to avoid hypothermia or intergroup temperature differ ences, and blood pressure was regulated to 60 mmHg. The entire brain w as subserially sectioned, and 52 standardized coronal sections encompa ssing the infarct were examined histologically 2 wk after the ischemia . Animals were randomized to receive either (+-5-methyl-10, 11-dihydro -5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) 1 mg/kg of maleate sal t or carrier solution, 20 min and again at 12 h after the onset of isc hemia. Cingulate and retrosplenial cortex were examined for NMDA-antag onist-induced neuronal necrosis. No reduction, or trend toward reducti on of neurobehavioral deficit was seen with MK-801. MCA occlusion redu ced EEG power over the ischemic hemisphere. MK-801 appeared to cause b rain activation, and globally increased power at several frequencies. MK-801 did not reduce infarction in either neocortex (p > 0.05) or str iatum (p > 0.05). No selective neuronal necrosis was seen in the cingu late or retrosplenial cortex. We conclude that MK-801 given 20 min aft er the onset of transient ischemia offers no significant neuroprotecti ve effect against either neurobehavioral deficit or ischemic infarctio n in this model of transient focal ischemia. Further experiments in un anesthetized animals are necessary to determine if MK-801-induced necr osis exists in the gyrencephalic brain, but the enhancement of primate brain electrical activity by MK-801 suggests that brain activation oc curs in primates as it does in rodents.