The effect of selective group I metabotropic glutamate receptor subtype 5 (mGluR5) antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB-1893) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. Treatment with MPEP and SIB-1893 showed significant neuroprotective effects in rat cortical neuronal cultures subjected to mechanical injury. Application of the antagonists also attenuated glutamate- and N-methyl-D-aspartate (NMDA)-induced neuronal cell death in vitro. Intracerebroventricular administration of MPEP to rats markedly improved motor recovery and reduced deficits of spatial learning after lateral fluid percussion-induced traumatic brain injury. Lesion volumes as assessed by magnetic resonance imaging were also substantially reduced by MPEP treatment. Although we show that MPEP acts as a potent mGluR5 antagonist in our culture system, where it completely blocks agonist-induced phosphoinositide hydrolysis, electrophysiological and pharmacological studies indicate that MPEP and SIB-1893 also inhibit NMDA receptor activity at higher concentrations that are neuroprotective. Taken together, these data suggest that MPEP and SIB-1893 may have therapeutic potential in brain injury, although the mechanisms of neuroprotective action for these drugs may reflect their ability to modulate NMDA receptor activity.


  • Animals, Brain Injuries, Cell Survival, Cells, Cultured, Cerebral Cortex, Electrophysiology, Excitatory Amino Acid Antagonists, Glutamic Acid, Hydrolysis, Male, Maze Learning, Memory, N-Methylaspartate, Neurons, Neuroprotective Agents, Phosphatidylinositols, Pyridines, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Receptors, N-Methyl-D-Aspartate, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.
Original languageEnglish
Pages (from-to)41-7
Number of pages7
JournalThe Journal of pharmacology and experimental therapeutics
Issue number1
Publication statusPublished - Jan 2001

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