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Volume 16, Number 19, Issue of October 1, 1996 pp. 6012-6020
Copyright ©1996 Society for Neuroscience

Activation of Metabotropic Glutamate Receptor Subtype mGluR1 Contributes to Post-Traumatic Neuronal Injury

Received April 2, 1996; revised June 28, 1996; accepted July 19, 1996.

Alexey Mukhin¹, Lei Fan¹, and Alan I. Faden²

¹ Department of Neurology and the Institute for Cognitive and Computational Sciences, and ² Departments of Neurology and Pharmacology and the Institute for Cognitive and Computational Sciences, Georgetown University Medical Center, Washington, DC 20007-2197

The role of phospholipase C-coupled (group I) metabotropic glutamate receptors (mGluR1 and mGluR5) in post-traumatic neuronal injury was examined using rat in vivo and in vitro models. Traumatic injury to mixed neuronal/glial cultures induced phosphoinositide hydrolysis and caused neuronal death. Pharmacological blockade of group I receptors significantly reduced these effects in vitro and decreased neurological deficits as well as neuronal loss produced by traumatic brain injury in vivo. In contrast, activation of group I receptors by a specific agonist in vitro exacerbated post-traumatic neuronal death in a dose-dependent manner. Antisense oligodeoxynucleotide directed to mGluR1, but not to mGluR5, was neuroprotective in vitro, although each oligodeoxynucleotide reduced the respective receptor-stimulated accumulation of inositol phosphates to a similar degree. Together, these findings suggest that activation of mGluR1 contributes to post-traumatic neuronal injury and that mGluR1 antagonists may have therapeutic potential in brain injury.

Key words: antisense oligodeoxynucleotides; brain trauma; metabotropic glutamate receptors; neuronal injury; neuroprotection; phosphoinositide hydrolysis

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