TY - JOUR

T1 - 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

AU - Movsesyan, V A

AU - O'Leary, D M

AU - Fan, L

AU - Bao, W

AU - Mullins, P G

AU - Knoblach, S M

AU - Faden, A I

PY - 2001/1

Y1 - 2001/1

N2 - 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.

AB - 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.

KW - Animals

KW - Brain Injuries

KW - Cell Survival

KW - Cells, Cultured

KW - Cerebral Cortex

KW - Electrophysiology

KW - Excitatory Amino Acid Antagonists

KW - Glutamic Acid

KW - Hydrolysis

KW - Male

KW - Maze Learning

KW - Memory

KW - N-Methylaspartate

KW - Neurons

KW - Neuroprotective Agents

KW - Phosphatidylinositols

KW - Pyridines

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptor, Metabotropic Glutamate 5

KW - Receptors, Metabotropic Glutamate

KW - Receptors, N-Methyl-D-Aspartate

KW - Journal Article

KW - Research Support, U.S. Gov't, Non-P.H.S.

KW - Research Support, U.S. Gov't, P.H.S.

M3 - Article

C2 - 11123360

VL - 296

SP - 41

EP - 47

JO - The Journal of pharmacology and experimental therapeutics

JF - The Journal of pharmacology and experimental therapeutics

SN - 0022-3565

IS - 1

ER -