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 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.