MK-801 and memantine protect cultured neurons from glutamate toxicity induced by glutamate carboxypeptidase-mediated cleavage of methotrexate.
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 microM. 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-asparate receptor antagonists should be coadministered in future experimental and clinical trials examining intrathecal glutamate carboxypeptidase rescue of methotrexate toxicity.
Weller
M
M
Section on Molecular Pharmacology, National Institute of Mental Health, Bethesda, MD.
Marini
A M
AM
Finiels-Marlier
F
F
Martin
B
B
Paul
S M
SM
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects*; D002268:Carboxypeptidases / Q000494:pharmacology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000633:toxicity*; D018698:Glutamic Acid; D008559:Memantine / Q000494:pharmacology*; D008727:Methotrexate / Q000378:metabolism / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D002268:Carboxypeptidases; C026134:glutamate carboxypeptidase; D008559:Memantine; D008727:Methotrexate