Toxicity induced by a polyglutamated folate analog is attenuated by NAALADase inhibition.
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 microM). 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 microM-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.
Thomas
A G
AG
Guilford Pharmaceuticals, 6611 Tributary Street, Baltimore, MD 21224, USA.
Olkowski
J L
JL
Vornov
J J
JJ
Slusher
B S
BS
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D003847:Deoxyglucose / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D043425:Glutamate Carboxypeptidase II; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011190:Potassium Cyanide / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats
C402107:2-(phosphonomethyl)pentanedioic acid; C402928:4-amino-10-methylpteroylhexa-gamma-glutamic acid; D001565:Benzoates; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D009943:Organophosphorus Compounds; D011759:Pyrrolidines; C079694:alpha-methyl-4-carboxyphenylglycine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C043250:pyrrolidin-3-yl-methanesulfonic acid; D003847:Deoxyglucose; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II; D011190:Potassium Cyanide; D005998:Glycine; D008727:Methotrexate