DCG-IV selectively attenuates rapidly triggered NMDA-induced neurotoxicity in cortical neurons

Eur J Neurosci. 1996 Jan;8(1):138-43. doi: 10.1111/j.1460-9568.1996.tb01174.x.

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

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Bucladesine / pharmacology
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / drug effects
  • Cyclic AMP / metabolism
  • Cyclopropanes / pharmacology*
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Kainic Acid / pharmacology
  • Membrane Potentials / drug effects
  • Mice
  • N-Methylaspartate / antagonists & inhibitors
  • N-Methylaspartate / toxicity*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / physiology
  • Neurotoxins / antagonists & inhibitors
  • Neurotoxins / toxicity*
  • Pertussis Toxin
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, Metabotropic Glutamate / physiology
  • Virulence Factors, Bordetella / pharmacology
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

  • Cyclopropanes
  • Neurotoxins
  • Receptors, Metabotropic Glutamate
  • Virulence Factors, Bordetella
  • 2-(2,3-dicarboxycyclopropyl)glycine
  • N-Methylaspartate
  • Bucladesine
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Cyclic AMP
  • Pertussis Toxin
  • Kainic Acid
  • Glycine