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
L. Massieu et al., 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, Neuroscience, 55(4), 1993, pp. 883-892
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.