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

M. Chen, R. Bullock, D. I. Graham, P. Frey, D. Lowe, J. McCulloch

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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 occlusion 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 μg/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 μg/ml during the initial 120 minutes after the middle cerebral artery occlusion. Treatment with D-CPPene (15 mg/kg, plus an infusion of 170 μg/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.

Original languageEnglish (US)
Pages (from-to)62-70
Number of pages9
JournalAnnals of neurology
Volume30
Issue number1
DOIs
StatePublished - Jul 1991

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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