NAALADase inhibition protects motor neurons against chronic glutamate toxicity

Ajit G. Thomas, Andrea M. Corse, Carol F. Coccia, Masako M. Bilak, Jeffrey D. Rothstein, Barbara S. Slusher

Research output: Contribution to journalArticlepeer-review

Abstract

Glutamate toxicity is implicated in the pathogenesis of amyotrophic lateral sclerosis. The neuropeptide N-acetyl-aspartyl glutamate (NAAG) appears to function both as a storage form for glutamate and as a neuromodulator at glutamatergic synapses. N-acetylated-α-linked acidic dipeptidase (NAALADase; also termed glutamate carboxypeptidase II) yields N-acetyl aspartate (NAA) and glutamate. Prior studies have demonstrated NAALADase upregulation in motor cortex and increased NAAG, NAA and glutamate in cerebrospinal fluid from amyotrophic lateral sclerosis patients. The potent NAALADase inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), was tested in an in vitro model of chronic glutamate-mediated motor neuron degeneration. Neuroprotection was determined (1) biochemically, by measuring choline acetyltransferase activity, (2) immunohistochemically, by counting neurofilament-H-positive motor neurons and (3) morphologically, with phase contrast microscopy. 2-PMPA (10 μM) had significant neuroprotective effects on motor neurons as evidenced by increased choline acetyltransferase activity, decreased motor neuron loss and improved gross morphology. Results suggest that NAALADase inhibitors protect against chronic glutamate-mediated motor neuron degeneration and may prove therapeutic towards amyotrophic lateral sclerosis.

Original languageEnglish (US)
Pages (from-to)177-184
Number of pages8
JournalEuropean Journal of Pharmacology
Volume471
Issue number3
DOIs
StatePublished - Jun 27 2003

Keywords

  • Amyotrophic lateral sclerosis
  • GCP II
  • Glutamate
  • Motor neuron disorder
  • NAAG
  • NAALADase
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmacology

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