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Journal of Neuroscience, Vol 8, 185-196, Copyright © 1988 by Society for Neuroscience
Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists
DW Choi, JY Koh and S Peters
Department of Neurology, Stanford University Medical Center, California 94305.
The antagonist pharmacology of glutamate neurotoxicity was quantitatively
examined in murine cortical cell cultures. Addition of 1- 3 mM
DL-2-amino-5-phosphonovalerate (APV), or its active isomer D-APV, acutely
to the exposure solution selectively blocked the neuroexcitation and
neuronal cell selectively blocked the neuroexcitation and neuronal cell
loss produced by N-methyl-D-aspartate (NMDA), with relatively little effect
on that produced by either kainate or quisqualate. As expected, this
selective NMDA receptor blockade only partially reduced the neuroexcitation
or acute neuronal swelling produced by the broad-spectrum agonist
glutamate; surprisingly, however, this blockade was sufficient to reduce
glutamate- induced neuronal cell loss markedly. Lower concentrations of APV
or D- APV had much less protective effect, suggesting that the blockade of
a large number of NMDA receptors was required to acutely antagonize
glutamate neurotoxicity. This requirement may be caused by the
amplification of small amounts of acute glutamate-induced injury by
subsequent release of endogenous NMDA agonists from injured neurons, as the
"late" addition of 10-1000 microM APV or D-APV (after termination of
glutamate exposure) also reduced resultant neuronal damage. If APV or D-APV
were present both during and after glutamate exposure, a summation
dose-protection relationship was obtained, showing substantial protective
efficacy at low micromolar antagonist concentrations. Screening of several
other excitatory amino acid antagonists confirmed that the ability to
antagonize glutamate neurotoxicity might correlate with ability to block
NMDA-induced neuroexcitation: The reported NMDA antagonists ketamine and
DL-2-amino- 7-phosphono-heptanoate, as well as the broad-spectrum
antagonist kynurenate, were all found to attenuate glutamate neurotoxicity
substantially; whereas gamma-D-glutamylaminomethyl sulfonate and L-
glutamate diethyl ester, compounds reported to block predominantly
quisqualate or kainate receptors, did not affect glutamate neurotoxicity.
The present study suggests that glutamate neurotoxicity may be
predominantly mediated by the activation of the NMDA subclass of glutamate
receptors--occurring both directly, during exposure to exogenous compound,
and indirectly, due to the subsequent release of endogenous NMDA agonists.
Given other studies linking NMDA receptors to channels with unusually high
calcium permeability, this suggestion is consistent with previous data
showing that glutamate neurotoxicity depends heavily on extracellular
calcium.
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