Abstract
Sodium-dependent, high-affinity glutamate transport is generally assumed to limit the toxicity of glutamate in vivo and in vitro, but there is very little direct evidence to support this hypothesis. In the present study, the effects of the specific uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate on the toxicity and clearance of glutamate were examined in hippocampal neuronal cultures. At a concentration that was not toxic by itself, L-trans-pyrrolidine-2,4-dicarboxylate increased the toxicity of glutamate approximately fivefold and slowed the clearance of glutamate from the extracellular space. This toxicity was almost completely blocked by the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonopentanoate. These studies provide direct evidence that sodium-dependent, high-affinity glutamate transport limits glutamate toxicity in vitro.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Biological Transport / drug effects
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Cells, Cultured
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Dicarboxylic Acids / pharmacology*
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Drug Synergism
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Embryo, Mammalian
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Female
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Glutamates / metabolism*
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Glutamates / toxicity*
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Glutamic Acid
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Hippocampus / drug effects*
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Hippocampus / metabolism
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Hippocampus / pathology
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Kinetics
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Macrophages / drug effects
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Macrophages / metabolism
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Neuroglia / drug effects
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Neuroglia / metabolism
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Neurons / drug effects*
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Neurons / metabolism
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Neurons / pathology
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Neurotoxins / toxicity*
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Pregnancy
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Pyrrolidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Valine / analogs & derivatives
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Valine / pharmacology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Dicarboxylic Acids
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Glutamates
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Neurotoxins
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Pyrrolidines
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Receptors, N-Methyl-D-Aspartate
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Glutamic Acid
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2-amino-5-phosphopentanoic acid
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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pyrrolidine-2,4-dicarboxylic acid
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Valine