Vol. 296, Issue 1, 41-47, January 2001

mGluR5 Antagonists 2-Methyl-6-(phenylethynyl)-pyridine and (E)-2-Methyl-6-(2-phenylethenyl)-pyridine Reduce Traumatic Neuronal Injury In Vitro and In Vivo by Antagonizing N-Methyl-D-aspartate Receptors

Vilen A. Movsesyan, Deirdre M. O'Leary, Lei Fan, Weili Bao, Paul G. M. Mullins, Susan M. Knoblach and Alan I. Faden

Georgetown Institute for Cognitive and Computational Sciences, Department of Neuroscience, Georgetown University Medical Center, Washington, DC

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.