EFFICACY OF D-CPPENE, A COMPETITIVE N-METHYL-D-ASPARTATE ANTAGONIST IN FOCAL CEREBRAL-ISCHEMIA IN THE RAT

The effect of a novel and potent competitive N-methyl-D-aspartate (NMDA) antagonist D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPPene) upon ischemic brain damage has been examined in a rat model of focal cerebral ischemia. Focal cerebral ischemia was produced by permanent occlusion of the left middle cerebral artery (MCA). The animals were sacrificed 24 h after MCA occlusion and the amount of ischemic brain damage was assessed at 8 predetermined coronal planes. Pretreatment with D-CPPene (1.5. 4.5 or 15 mg/kg, i.v.), initiated 15 min prior to MCA occulusion (followed by constant infusion at 1, 3 or 10 mg/kg/h), produced dose-dependent reductions in the volumes of infarction; the dose of 4.5 mg/kg being the most effective (reduced by 37%: P<0.01). These results indicate that systemic administration of the competitive NMDA antagonist D-CPPene has neuroprotective effects in a model of focal cerebral ischemia and define the dose dependency of its neuroprotective effects.