Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury.
We examined the effects of modulating group II metabotropic glutamate receptors (mGluRs) on traumatic neuronal injury using both in vitro and in vivo models. Treatment with various selective group II mGluR agonists significantly decreased lactate dehydrogenase release, a marker of cell death, after traumatic injury to rat neuronal-glial cultures; injury-induced increases in cyclic AMP and glutamate levels were also significantly reduced by a group II agonist. The neuroprotective effects of group II agonists were markedly attenuated by coadministration of a group II antagonist or a membrane-permeable cyclic AMP analog and were additive to those provided by an N-methyl-D-aspartate receptor antagonist or a selective group I mGluR antagonist. Administration of a group II mGluR agonist 30 min after lateral fluid percussion-induced brain injury in rats significantly improved subsequent behavioral recovery as compared with vehicle-treated controls. Together these studies indicate that group II mGluR agonists protect against traumatic neuronal injury by attenuating glutamate release and cAMP levels and suggest a potential role for these agents in the treatment of clinical neurotrauma.
Allen
J W
JW
Institute for Cognitive and Computational Sciences and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, D.C., USA.
Ivanova
S A
SA
Fan
L
L
Espey
M G
MG
Basile
A S
AS
Faden
A I
AI
D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005971:Glutamates / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors*
D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; C104753:eglumetad