Evaluation of a competitive NMDA antagonist (D‐CPPene) in feline focal cerebral ischemia

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Abstract
The effects of a competitive, N‐methyl‐D‐aspartate (NMDA) receptor antagonist, D(‐)E‐4‐(3‐phosphonoprop‐2‐enyl)‐piperazine‐2‐carboxylic acid (D‐CPPene), on the volume of ischemic brain damage was assessed by quantitative histological study in 35 chloralose‐anesthetized cats. Focal cerebral ischemia was produced by permanent occulsion of one middle cerebral artery and the animals were killed by transcardiac perfusion fixation 6 hours later. Pretreatment with D‐CPPene (1.5, 4.5, or 15 mg/kg, administered intravenously 15 minutes prior to occlusion, with subsequent drug infusions to maintain a plateau in the plasma drug concentrations) effected dose‐dependent reductions in the volume of ischemic brain damage. At the highest dose studied (15 mg/kg, plus an infusion of 170 m̈g/kg/min), D‐CPPene reduced the volume of ischemic damage in the cerebral cortex by more than 75% compared to vehicle‐treated control animals. The plasma concentration of D‐CPPene, which is associated with a half maximal reduction in the volume of ischemic damage, was estimated to be 24 m̈g/ml during the initial 120 minutes after the middle cerebral artery occlusion. Treatment with D‐CPPene (15 mg/kg, plus an infusion of 170 m̈g/kg/min) initiated 1 hour after occlusion reduced the volume of ischemic brain damage in the cerebral cortex by 30%, but this response did not achieve statistical significance. Precise definition of dose dependency for the anti‐ischemic effects of NMDA antagonists and the therapeutic time window are influenced greatly by brain pharmacokinetics of the agents. Such data are crucial if the potent anti‐ischemic effects of NMDA antagonists observed in animals are to be translated into meaningful clinical evaluation of such agents in stroke and head trauma.