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

Folates have been shown to be neurotoxic and convulsive. Endogenously, fola tes exist in the brain in a polyglutamated form with 1-7 terminal glutamate s (approx. 1 mu M). The brain enzyme N-acetylated alpha-linked acidic dipep tidase (NAALADase) has been shown to remove sequentially the gamma-linked g lutamates from folic acid polyglutamates. We report that, at high concentra tions (300 mu M-30 mM), a folic acid hexaglutamate analog is dose-dependent ly toxic to dissociated rat cortical cultures and that this toxicity is rev ersed by 2-PMPA, a potent and selective NAALADase inhibitor. These data sug gest a new mechanism for folic acid toxicity. (C) 1999 Elsevier Science B.V . All rights reserved.