MK-801 and memantine protect cultured neurons from glutamate toxicity induced by glutamate carboxypeptidase-mediated cleavage of methotrexate

Michael Weller, Ann M. Marini, Françoise Finiels-Marlier, Brian Martin, Steven M. Paul

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Cleavage of methotrexate into glutamate and diaminomethylpteroate by intrathecal glutamate carboxypeptidase is a new approach to the treatment of acute methotrexate neurotoxicity. The simulation of glutamate carboxypeptidase rescue from high-dose methotrexate in neuron astrocyte cocultures of rat cerebellum or cerebral cortex resulted in a selective, concentration-dependent neurotoxicity. The neurotoxicity was caused by the enzymatic release of glutamate from methotrexate at lower concentrations of methotrexate, and by both glutamate and diaminomethylpteroate at concentrations of methotrexate exceeding 200 μM. The good neuroprotection afforded by MK-801 and memantine suggested that glutamate toxicity was mediated by N-methyl-D-aspartate receptors. Methotrexate alone was not toxic to astrocytes, neurons, or the neurite networking. [3H]thymidine and [3H]deoxyuridine incorporation studies showed that astrocyte proliferation in the presence of methotrexate was maintained by the reutilization of pyrimidine bases for DNA synthesis. N-methyl-D-aspartate receptor antagonists should be coadministered in future experimental and clinical trials examining intrathecal glutamate carboxypeptidase rescue of methotrexate toxicity.

Original languageEnglish
Pages (from-to)303-312
Number of pages10
JournalEuropean Journal of Pharmacology: Environmental Toxicology and
Volume248
Issue number4
DOIs
StatePublished - Dec 1 1993
Externally publishedYes

Keywords

  • Carboxypeptidase
  • Glutamate
  • MK-801
  • Memantine
  • Methotrexate
  • Neurotoxicity

Fingerprint Dive into the research topics of 'MK-801 and memantine protect cultured neurons from glutamate toxicity induced by glutamate carboxypeptidase-mediated cleavage of methotrexate'. Together they form a unique fingerprint.

  • Cite this