Ek. Speliotes et al., COMPARISON OF THE POTENCY OF COMPETITIVE NMDA ANTAGONISTS AGAINST THENEUROTOXICITY OF GLUTAMATE AND NMDA, Journal of neurochemistry, 63(3), 1994, pp. 879-885
The object of this investigation was to determine whether glutamate up
take affects the apparent potency of the competitive antagonists DL-2-
amino-5-phosphonovalerate and CGS-19755 in blocking NMDA receptor-medi
ated neurotoxicity. In astrocyte-rich rat cortical cultures we observe
d that DL-2-amino-5-phosphonovalerate and CGS-19755 were 24 and 16 tim
es more potent against NMDA than against glutamate-induced toxicity. I
n contrast, DL-2-amino-5-phosphonovalerate was equipotent against the
two agonists in astrocyte-poor cultures, in which dendrites are direct
ly exposed to the ex tracellular medium. With the noncompetitive NMDA
antagonist MK-801, similar potencies were observed against glutamate (
212 +/- 16 nM) and against NMDA (155 +/- 9 nM) neurotoxicity. These re
sults may be explained if we assume that the neuronal cell body is les
s susceptible than the dendrites to NMDA receptor-mediated toxicity, a
nd that the action of glutamate in astrocyte-rich cultures is confined
to the cell body. In this case, one would expect that higher concentr
ations of glutamate would be needed to produce toxicity in astrocyte-r
ich cultures, and that higher concentrations of competitive antagonist
s would be needed to overcome this toxicity. Our observations help exp
lain the pharmacology of the competitive NMDA antagonists against NMDA
receptor-mediated neurotoxicity but also suggest the possibility that
, because the cell body and dendrites may be distinct sites for neurot
oxicity, they might also involve different mechanisms of toxicity.