Plasma and CSF levels of dizocilpine (MK-801) required for neuroprotection in the quinolinate-injected rat striatum.

This study has identified the range of plasma and cerebrospinal fluid (CSF) concentrations of the uncompetitive N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) required for neuroprotection in the quinolinate-lesioned rat striatum. Dizocilpine was given i.v. as a bolus injection followed by a continuous infusion for 4 h, drug administration starting 30 min after a unilateral, intrastriatal injection of 200 nmol quinolinate. Neurodegeneration was assessed 7 days later in striatal homogenates by measuring the activities of the enzymes choline acetyltransferase and glutamate decarboxylase. Stable plasma levels of dizocilpine were achieved over the 4 h of infusion and the drug appeared rapidly in the CSF to reach steady state levels which were approximately 50% of the corresponding plasma values. When the degree of drug bound to plasma and CSF protein (as determined in in vitro experiments with [3H]dizocilpine) was taken into account, the steady state plasma and CSF concentrations were equivalent, indicating free exchange of dizocilpine between these compartments. A small, but significant, neuroprotective effect with respect to both enzyme markers was obtained with free steady state plasma and CSF concentrations of 24 and 21 nM. A high degree of neuroprotection occurred with steady state plasma and CSF concentrations of 47 and 40 nM, respectively, which was not improved by raising the dizocilpine concentration in these compartments further, indicating a maximal effect. The CSF concentrations required for neuroprotection in this model are close to the known affinity of dizocilpine for the N-methyl-D-aspartate receptor as determined in in vitro experiments.(ABSTRACT TRUNCATED AT 250 WORDS)