Evaluation of a competitive NMDA antagonist (D-CPPene) in feline focal cerebral ischemia.
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 micrograms/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 micrograms/ml during the initial 120 minutes after the middle cerebral artery occlusion. Treatment with D-CPPene (15 mg/kg, plus an infusion of 170 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Chen
M
M
Wellcome Neuroscience Group, University of Glasgow, United Kingdom.
Bullock
R
R
Graham
D I
DI
Frey
P
P
Lowe
D
D
McCulloch
J
J
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology* / Q000517:prevention & control; D002415:Cats; D002421:Caudate Nucleus / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004334:Drug Administration Schedule; D006207:Half-Life; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C065286:SDZ EAA 494; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate