Antagonists for group I mGluRs attenuate excitotoxic neuronal death in cortical cultures.
Activation of ion channel-linked glutamate receptors, especially N-methyl-D-aspartate (NMDA) receptors, mediates the excitotoxic effects of glutamate upon central neurons. We examined the hypothesis that activation of group I metabotropic glutamate receptors (mGluRs) would increase NMDA receptor-mediated cortical neuronal death. Addition of the selective group I mGluR agonists, dihydroxyphenylglycine (DHPG) or trans-azetidine-2,4-dicarboxylic acid (t-ADA) potentiated NMDA-induced neuronal death, and application of the group I mGluR-selective antagonist, aminoindan-1,5-dicarboxylic acid (AIDA), as well as the non-selective antagonists methyl-4-carboxyphenylglycine (MCPG) or 4-carboxyphenylglycine (4CPG) reduced NMDA- and kainate-induced neuronal death in murine cortical cultures. The pro-excitotoxic effect of group I mGluR activation may be mediated largely by enhancement of glutamate release, as DHPG potentiated high potassium-stimulated glutamate release, and the protective effects of both AIDA and MCPG were abolished when NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors were blocked immediately after toxic NMDA receptor overstimulation. The present data support the possibility that antagonizing group I mGluRs may be a useful strategy for attenuating excitotoxic neuronal death in certain disease states.
Strasser
U
U
Department of Neurology, Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA.
Lobner
D
D
Behrens
M M
MM
Canzoniero
L M
LM
Choi
D W
DW
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001565:Benzoates / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000032:analysis / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D018091:Receptors, AMPA / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
C095756:1-aminoindan-1,5-dicarboxylic acid; D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D018377:Neurotransmitter Agents; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; D018698:Glutamic Acid; D016202:N-Methylaspartate; C079693:4-carboxyphenylglycine; D005998:Glycine