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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleNEUROPHARMACOLOGY

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 AntagonizingN-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
Journal of Pharmacology and Experimental Therapeutics January 2001, 296 (1) 41-47;
Vilen A. Movsesyan
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Deirdre M. O'Leary
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Lei Fan
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Weili Bao
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Paul G. M. Mullins
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Susan M. Knoblach
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Alan I. Faden
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Abstract

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- andN-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.

Footnotes

  • Send reprint requests to: Alan I. Faden, M.D., Georgetown Institute for Cognitive and Computational Sciences, Department of Neuroscience, Georgetown University Medical Center, 3900 Reservoir Rd. N.W., Research Bldg., Rm. EP12, Washington, DC 20007. E-mail:fadena{at}giccs.georgetown.edu

  • This study was supported by grants from the National Institutes of Health (RO1NS37313) and the Department of Defense (DAMD-17-93-V-3018).

  • Abbreviations:
    mGluR
    metabotropic glutamate receptor
    IP
    inositol phosphate(s)
    MPEP
    2-methyl-6-(phenylethynyl)-pyridine
    SIB-1893
    (E)-2-methyl-6-(2-phenylethenyl)-pyridine
    TBI
    traumatic brain injury
    NMDA
    N-methyl-d-aspartate
    DIV
    day in vitro
    CHPG
    (R,S)-2-chloro-5-hydroxyphenylglycine
    LDH
    lactate dehydrogenase
    MRI
    magnetic resonance imaging
    PI
    phosphoinositide
    MK801
    (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
    TR/TE
    repetition time/echo time
    RARE
    rapid acquisition with relaxation enhancement
    • Received June 13, 2000.
    • Accepted September 14, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 1
1 Jan 2001
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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 AntagonizingN-Methyl-d-aspartate Receptors
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Research ArticleNEUROPHARMACOLOGY

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 AntagonizingN-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
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 41-47;

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Research ArticleNEUROPHARMACOLOGY

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 AntagonizingN-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
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 41-47;
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