mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and invivo by antagonizing N-methyl-D-aspartate receptors

The effect of selective group I metabotropic glutamate receptor subtype 5 ( mGluR5) antagonists 2-methyl-6-(phenylethynyl) pyridine (MPEP) and (E)-2-me thyl-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-as partate (NMDA)-induced neuronal cell death in vitro. Intracerebroventricula r administration of MPEP to rats markedly improved motor recovery and reduc ed deficits of spatial learning after lateral fluid percussion-induced trau matic brain injury. Lesion volumes as assessed by magnetic resonance imagin g were also substantially reduced by MPEP treatment. Although we show that MPEP acts as a potent mGluR5 antagonist in our culture system, where it com pletely blocks agonist-induced phosphoinositide hydrolysis, electrophysiolo gical and pharmacological studies indicate that MPEP and SIB-1893 also inhi bit NMDA receptor activity at higher concentrations that are neuroprotectiv e. Taken together, these data suggest that MPEP and SIB-1893 may have thera peutic potential in brain injury, although the mechanisms of neuroprotectiv e action for these drugs may reflect their ability to modulate NMDA recepto r activity.