L-cycloserine: a potent anticonvulsant

The L-isomer of 4-amino-3- isoxazolidinone (L-cycloserine), a potent transaminase inhibitor, was tested for its anticonvulsant action. Intraperitoneal injection of 25 mg kg-1 protects the inbred epileptic mouse (DBA/2J) from convulsions. The drug exerts its protective influence 3 h after administration, and its effect subsides gradually thereafter. A normal mouse (CBA/CA) can be made prone to sound-induced epilepsy by enhancing its cerebral concentrations of Zn2+ and pyridoxal-5'-phosphate (PLP). Prior administration of 25-50 mg kg-1 L-cycloserine counteracts the convulsive effects of these substances. The pretreated animal is resistant to seizures. The concentrations of glutamate and aspartate in the inferior colliculus of the treated animal are diminished, whereas the concentration of gamma-aminobutyrate is enhanced. The time course of the changes in the amino acid concentrations broadly mirrors the changes in seizure susceptibility following the treatment. Proton nuclear magnetic resonance spectra of a mixture containing equimolar concentrations of L-cycloserine, PLP, and ZnSO4 were obtained. From the resonance peaks of such an adduct, we have ascertained that a molecule of L-cycloserine forms an irreversible Schiff base with the 4-aldehyde group of PLP, and this adduct is stabilized by a zinc ion. The significance of this finding for the anticonvulsant action of the drug is discussed.