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

• Published in: Brain research Vol. 843; no. 1; pp. 48 - 52
• Main Authors: Thomas, Ajit G, Olkowski, Jennifer L, Vornov, James J, Slusher, Barbara S
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 02.10.1999; Amsterdam Elsevier; New York, NY
• Subjects: 2-PMPA; 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; Animals; Benzoates - pharmacology; Biochemistry and metabolism; Biological and medical sciences; Carboxypeptidases - antagonists & inhibitors; Cells, Cultured; Central nervous system; Cerebral Cortex - cytology; Cerebral Cortex - physiology; Deoxyglucose - pharmacology; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Fetus; Fundamental and applied biological sciences. Psychology; Glutamate Carboxypeptidase II; Glycine - analogs & derivatives; Glycine - pharmacology; In vitro; Methotrexate - analogs & derivatives; Methotrexate - antagonists & inhibitors; Methotrexate - toxicity; Methotrexate hexaglutamate; N-Acetylated alpha-linked acidic dipeptidase; N-Methylaspartate - pharmacology; NAALADase; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Neurotoxicity; Neurotoxins - toxicity; Organophosphorus Compounds - pharmacology; Potassium Cyanide - pharmacology; Pyrrolidines - pharmacology; Rats; Vertebrates: nervous system and sense organs; 2-PMPA; Methotrexate hexaglutamate; Neurotoxicity; NAALADase; In vitro; Cerebral cortex; Rat; Enzyme; Toxicity; Rodentia; Central nervous system; Glutamate; Folic acid; Vertebrata; Mammalia; Analog; Excitatory aminoacid; Neurotransmitter; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(99)01879-X

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.