Abstract
Molecular cloning has revealed the existence of at least eight subtypes of metabotropic glutamate receptors (mGluRs). We examined the effect of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), a selective agonist of the mGluR 2/3 subtype, on excitotoxicity in mouse cortical cell cultures. Addition of DCG-IV to the exposure medium partially attenuated the rapidly triggered excitotoxic death induced by a 5 min exposure to 200 microM NMDA. This neuroprotective effect was reversed by coapplication of alpha-methyl-4-carboxyphenylglycine (MCPG), an antagonist of mGluRs, by pertussis toxin pretreatment and also by preincubation with dibutyryl cAMP, a stable analogue of cAMP. These results suggest that the activation of mGluR 2/3 is neuroprotective in our system. However, DCG-IV did not attenuate the slowly triggered neuronal death induced by 24 h exposure to low concentrations of NMDA, alpha-amino-1,3-cyclopentanedicarboxylic acid (AMPA) or kainate. The failure of DCG-IV to block slowly triggered NMDA neurotoxicity is likely due to weak NMDA agonist activity, as demonstrated in whole-cell recording.
MeSH terms
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6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
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Animals
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Bucladesine / pharmacology
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Cell Death / drug effects
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Cell Survival / drug effects
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Cells, Cultured
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Cerebral Cortex / cytology*
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Cerebral Cortex / drug effects
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Cyclic AMP / metabolism
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Cyclopropanes / pharmacology*
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Glycine / analogs & derivatives*
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Glycine / pharmacology
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Kainic Acid / pharmacology
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Membrane Potentials / drug effects
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Mice
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N-Methylaspartate / antagonists & inhibitors
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N-Methylaspartate / toxicity*
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Neurons / cytology
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Neurons / drug effects*
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Neurons / physiology
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Neurotoxins / antagonists & inhibitors
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Neurotoxins / toxicity*
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Pertussis Toxin
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Receptors, Metabotropic Glutamate / drug effects
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Receptors, Metabotropic Glutamate / physiology
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Virulence Factors, Bordetella / pharmacology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Cyclopropanes
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Neurotoxins
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Receptors, Metabotropic Glutamate
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Virulence Factors, Bordetella
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2-(2,3-dicarboxycyclopropyl)glycine
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N-Methylaspartate
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Bucladesine
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6-Cyano-7-nitroquinoxaline-2,3-dione
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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Cyclic AMP
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Pertussis Toxin
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Kainic Acid
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Glycine