Activation of metabotropic glutamate receptor subtype mGluR1 contributes to post-traumatic neuronal injury.
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.
Mukhin
A
A
Department of Neurology, Georgetown University Medical Center, Washington, DC 20007-2197, USA.
Fan
L
L
Faden
A I
AI
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D016923:Cell Death; D018920:Coculture Techniques; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D015151:Immunoblotting; D009417:Nerve Tissue / Q000293:injuries* / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology
D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C079694:alpha-methyl-4-carboxyphenylglycine; C079215:3,5-dihydroxyphenylglycine; D005998:Glycine