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

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

Fingerprint

Glutamate Carboxypeptidase II
Folic Acid
Glutamates
Polyglutamic Acid
Poisons
Brain
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Toxicity induced by a polyglutamated folate analog is attenuated by NAALADase inhibition. / Thomas, Ajit G.; Olkowski, Jennifer L.; Vornov, James J.; Slusher, Barbara.

In: Brain Research, Vol. 843, No. 1-2, 02.10.1999, p. 48-52.

Research output: Contribution to journalArticle

Thomas, Ajit G. ; Olkowski, Jennifer L. ; Vornov, James J. ; Slusher, Barbara. / Toxicity induced by a polyglutamated folate analog is attenuated by NAALADase inhibition. In: Brain Research. 1999 ; Vol. 843, No. 1-2. pp. 48-52.
@article{b8ec55e810ff4390a7c057436c7b85ea,
title = "Toxicity induced by a polyglutamated folate analog is attenuated by NAALADase inhibition",
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.",
keywords = "2-PMPA, In vitro, Methotrexate hexaglutamate, NAALADase, Neurotoxicity",
author = "Thomas, {Ajit G.} and Olkowski, {Jennifer L.} and Vornov, {James J.} and Barbara Slusher",
year = "1999",
month = "10",
day = "2",
doi = "10.1016/S0006-8993(99)01879-X",
language = "English (US)",
volume = "843",
pages = "48--52",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Toxicity induced by a polyglutamated folate analog is attenuated by NAALADase inhibition

AU - Thomas, Ajit G.

AU - Olkowski, Jennifer L.

AU - Vornov, James J.

AU - Slusher, Barbara

PY - 1999/10/2

Y1 - 1999/10/2

N2 - 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.

AB - 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.

KW - 2-PMPA

KW - In vitro

KW - Methotrexate hexaglutamate

KW - NAALADase

KW - Neurotoxicity

UR - http://www.scopus.com/inward/record.url?scp=0032832469&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032832469&partnerID=8YFLogxK

U2 - 10.1016/S0006-8993(99)01879-X

DO - 10.1016/S0006-8993(99)01879-X

M3 - Article

C2 - 10528109

AN - SCOPUS:0032832469

VL - 843

SP - 48

EP - 52

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 1-2

ER -