Journal of Neuroscience, Vol 10, 3970-3976, Copyright © 1990 by Society for Neuroscience
Dual effect of glycine on NMDA-induced neurotoxicity in rat cortical cultures
D McNamara and R Dingledine
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill 27599.
To examine the roles of glycine in neurotoxicity caused by NMDA, primary
rat cortical cultures were exposed to 100-300 microM NMDA plus glycine
(0-3000 microM) or other glycine analogs in a simple saline solution, and
toxicity was assessed by the amount of lactate dehydrogenase (LDH) released
from the cultures. NMDA-induced neurotoxicity was abolished by 100 microM
D-2-amino-5-phosphonovaleric acid (D-APV), phencyclidine (IC50, 4.1
microM), and Mg (IC50, 7.5 mM), or by reducing [Ca]0 to 0.1 mM.
NMDA-induced neurotoxicity could also be abolished by 7-chlorokynurenic
acid (IC50, 8.6 microM), suggesting the presence of residual glycine in the
culture medium (confirmed by high-performance liquid chromatography
measurement). Moreover, in the presence of 30 microM 7-chlorokynurenic
acid, glycine, D-serine, D- alanine, beta-fluoro-D-alanine, and
1-aminocyclopropanecarboxylic acid could restore the neurotoxic action of
NMDA, and their relative potencies and relative efficacies were the same as
measured in electrophysiological assays in Xenopus oocytes or cultured
neurons. The addition of greater than 100 microM glycine doubled the
excitotoxic effect of NMDA. The potency of glycine was low (EC50, 27
microM), and this effect was not due to a direct action on the NMDA
receptor. The above-mentioned agonists were unable to substitute for
glycine, even at high concentrations (1 mM). On the other hand,
beta-alanine, taurine, and GABA (1 mM) did potentiate NMDA neurotoxicity,
and strychnine (IC50, 550 nM) could greatly reduce neurotoxicity in the
presence of 1 mM glycine plus 300 microM NMDA.(ABSTRACT TRUNCATED AT 250
WORDS)
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