N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture

M. P. Goldberg, J. H. Weiss, P. C. Pham, D. W. Choi

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Abstract

The ability of several glutamate receptor antagonists to reduce hypoxic cortical neuronal injury was quantitatively examined in cell cultures derived from fetal mice. Cultures exposed to hypoxia for 8 hr showed by the following day widespread neuronal injury, which was substantially attenuated by addition of the specific N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV). The protective effect of APV was concentration dependent (ED50 about 2 μM) and stereospecific (D-APV) approximately 100 times more potent than L-APV). Neuron-protective effects were also observed with several other NMDA antagonists: 2-amino-7-phosphonoheptanoate, phencyclidine and (+)-SKF 10,047 [(+)-N-allylnormetazocine] - as well as with the nonspecific glutamate antagonists D-glutamylglycine and kynurenate. In addition, a similar antagonist profile was observed with a chemical model of hypoxic neuronal injury, produced by brief exposure to high concentrations of cyanide. In contrast, 1 mM concentrations of glutamate diethylester and γ-aminomethyl sulfonate, compounds reported in some studies to preferentially antagonize non-NMDA glutamate receptors, failed to protect neurons against either hypoxia or cyanide. These results are consistent with the hypothesis that NMDA receptors are preferentially involved in the pathogenesis of hypoxic cortical neuronal injury and suggest that cortical cell culture may be a useful system in which to quantitatively characterize the pharmacology of that injury.

Original languageEnglish (US)
Pages (from-to)784-791
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume243
Issue number2
StatePublished - 1987

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N-Methyl-D-Aspartate Receptors
Wounds and Injuries
Excitatory Amino Acid Antagonists
Cyanides
Cell Culture Techniques
Kynurenic Acid
Chemical Models
2-Amino-5-phosphonovalerate
D-Aspartic Acid
Neurons
Phencyclidine
Glutamate Receptors
N-Methylaspartate
Glutamic Acid
Pharmacology
Hypoxia

ASJC Scopus subject areas

  • Pharmacology

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N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture. / Goldberg, M. P.; Weiss, J. H.; Pham, P. C.; Choi, D. W.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 243, No. 2, 1987, p. 784-791.

Research output: Contribution to journalArticle

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