Antagonists for group I mGluRs attenuate excitotoxic neuronal death in cortical cultures

Authors

  • Uta Strasser,

    1. Department of Neurology, Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA
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  • Doug Lobner,

    1. Department of Neurology, Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA
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  • M. Margarita Behrens,

    1. Department of Neurology, Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA
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  • Lorella M. T. Canzoniero,

    1. Department of Neurology, Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA
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  • Dennis W. Choi

    1. Department of Neurology, Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA
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D. W. Choi, as above. E-mail: wildersp@neuro.wustl.edu

Abstract

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.

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