Toxicity induced by a polyglutamated folate analog is attenuated by NAALADase inhibition

Ajit G. Thomas, Jennifer L. Olkowski, James J. Vornov, Barbara S. Slusher

Research output: Contribution to journalArticle

Abstract

Folates have been shown to be neurotoxic and convulsive. Endogenously, folates exist in the brain in a polyglutamated form with 1-7 terminal glutamates (approx. 1 μM). The brain enzyme N-acetylated alpha-linked acidic dipeptidase (NAALADase) has been shown to remove sequentially the gamma- linked glutamates from folic acid polyglutamates. We report that, at high concentrations (300 μM-30 mM), a folic acid hexaglutamate analog is dose- dependently toxic to dissociated rat cortical cultures and that this toxicity is reversed by 2-PMPA, a potent and selective NAALADase inhibitor. These data suggest a new mechanism for folic acid toxicity.

Original languageEnglish (US)
Pages (from-to)48-52
Number of pages5
JournalBrain research
Volume843
Issue number1-2
DOIs
StatePublished - Oct 2 1999
Externally publishedYes

Keywords

  • 2-PMPA
  • In vitro
  • Methotrexate hexaglutamate
  • NAALADase
  • Neurotoxicity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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