Influence of picolinic acid on seizure susceptibility in mice

Background: The mechanism of drug resistance in epilepsy remains unknown. Picolinic acid (PIC) is an endogenous metabolite of the kynurenine pathway and a chelating agent added to dietary supplements. Both inhibitory and excitatory properties of PIC were reported. The aim of this study was to determine the influence of exogenously applied PIC upon the electroconvulsive threshold and the activity of chemical convulsants in eight models of epilepsy in mice. Methods: All experiments were performed on adult male Swiss albino mice. Electroconvulsions were induced through ear clip electrodes. The electroconvulsive threshold (current strength necessary to induce tonic seizures in 50% of the tested group - CS50) was estimated for control animals and animals pretreated with PIC. To determine the possible convulsant activity of PIC, it was administered subcutaneously or intracerebroventricularly in increasing doses to calculate the CD50 values (doses of convulsants necessary to produce seizures in 50% of the animals). Chemical convulsions were induced by challenging the animals with increasing doses of convulsant to calculate the CD50 values. The following convulsants were used: 4-aminopyridine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, bicuculline, N-methyl-D-aspartate, nicotine, pentylenetrazole, pilocarpine hydrochloride and strychnine nitrate. Results: PIC significantly decreased the electroconvulsive threshold and, after intracerebroventricular injection, but not subcutaneous, produced convulsions. Of the studied convulsants, only the activity of pilocarpine hydrochloride was significantly enhanced by PIC. Conclusions: PIC enhances seizure activity and potentially may play a role in the pathogenesis of drug resistant epilepsy. Future studies should focus on the interactions between PIC and antiepileptic drugs. (C) 2016 Published by Elsevier Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.