A COMPARATIVE-ANALYSIS OF THE NEUROPROTECTIVE PROPERTIES OF COMPETITIVE AND UNCOMPETITIVE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS IN-VIVO- IMPLICATIONS FOR THE PROCESS OF EXCITOTOXIC DEGENERATION AND ITS THERAPY

Injection of the N-methyl-D-aspartate receptor agonist, quinolinic aci d, into the rat striatum in vivo results in the degeneration of cholin ergic and GABAergic neurons, as deter-mined seven days later using the marker enzymes, choline acetyltransferase and glutamate decarboxylase , respectively. Such damage was dose-dependently prevented by CGP 3784 9 or MK-801 (competitive and uncompetitive N-methyl-D-aspartate recept or antagonists, respectively) administered systemically or intrastriat ally at the same time as quinolinic acid. The neuroprotective activity of CGP 37849 was associated with the D-enantiomer, CGP 40116 (ED507.5 mg/kg i.p.), which was approximately 1.5-fold and 3.5-fold more poten t than the related compounds, D-CPPene and CGS 19755, respectively. CG P 37849 was a weaker neuroprotectant than MK-801 (ED500.8 mg/kg i.p) w hen administered systemically, but was dramatically more potent follow ing coinjection with quinolinic acid (ED50's 0.2 and 117 nmol, respect ively). When injected intrastriatally 0.5-2 h post-quinolinic acid, CG P 37849 was protective over the entire period studied, whereas MK-801 was less effective at all post-quinolinic acid injection times. The fi nding that CGP 37849 is neuroprotective when administered intrastriata lly 1-2 h post-quinolinic acid supports the hypothesis that a period e xists following excitotoxic insult in which neurons are not committed to die, and can be rescued by blockade of ongoing N-methyl-D-aspartate receptor activation. Competition studies indicated that, when coinjec ted with 100-400 nmol quinolinic acid into the striatum, CGP 37849 exh ibited kinetics predicted of a competitive N-methyl-D-aspartate recept or antagonist (declining neuroprotective potency with increasing doses of agonist), whereas MK-801 displayed a complex picture, with weak pr otective activity at low doses of quinolinic acid. Following systemic administration, neither antagonist was markedly affected by the dose o f excitotoxin. When given i.p. at up to 6 h post-quinolinic acid, CGP 37849 and MK-801 showed essentially identical profiles of post-insult protection; degeneration of cholinergic neurons was reduced significan tly throughout the entire post-insult period, whereas GABAergic neuron s were protected only when drugs were administered 2 h or earlier post -quinolinic acid. The data indicate that competitive and uncompetitive N-methyl-D-aspartate receptor antagonists are effective neuroprotecta nts in vivo, and that parameters such as drug lipophilicity or mechani sm of action at the receptor do not impinge upon their properties as s ystemically active cerebroprotectants.