DCG-IV selectively attenuates rapidly triggered NMDA-induced neurotoxicity in cortical neurons.
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.
Buisson
A
A
Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
Yu
S P
SP
Choi
D W
DW
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D037342:Pertussis Toxin; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D003521:Cyclopropanes; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; D010566:Virulence Factors, Bordetella; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D016202:N-Methylaspartate; D003994:Bucladesine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000242:Cyclic AMP; D037342:Pertussis Toxin; D007608:Kainic Acid; D005998:Glycine