title: Comparison of the potency of competitive NMDA antagonists against the neurotoxicity of glutamate and NMDA.
abstract: The object of this investigation was to determine whether glutamate uptake affects the apparent potency of the competitive antagonists DL-2-amino-5-phosphonovalerate and CGS-19755 in blocking NMDA receptor-mediated neurotoxicity. In astrocyte-rich rat cortical cultures we observed that DL-2-amino-5-phosphonovalerate and CGS-19755 were 24 and 16 times more potent against NMDA than against glutamate-induced toxicity. In contrast, DL-2-amino-5-phosphonovalerate was equipotent against the two agonists in astrocyte-poor cultures, in which dendrites are directly exposed to the extracellular 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 results may be explained if we assume that the neuronal cell body is less susceptible than the dendrites to NMDA receptor-mediated toxicity, and that the action of glutamate in astrocyte-rich cultures is confined to the cell body. In this case, one would expect that higher concentrations of glutamate would be needed to produce toxicity in astrocyte-rich cultures, and that higher concentrations of competitive antagonists would be needed to overcome this toxicity. Our observations help explain 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 neurotoxicity, they might also involve different mechanisms of toxicity.
authors.affiliation: Department of Neurology, Children's Hospital, Boston, Massachusetts 02115.
authors.forename: E K
authors.initials: EK
authors.lastname: Speliotes
authors.forename: K A
authors.initials: KA
authors.lastname: Hartnett
authors.forename: R C
authors.initials: RC
authors.lastname: Blitzblau
authors.forename: E
authors.initials: E
authors.lastname: Aizenman
authors.forename: P A
authors.initials: PA
authors.lastname: Rosenberg
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001667:Binding, Competitive; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003712:Dendrites / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004622:Embryo, Mammalian; D005971:Glutamates / Q000633:toxicity*; D018698:Glutamic Acid; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D010875:Pipecolic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
chemical_list: D005971:Glutamates; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C053672:selfotel; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate