Topiramate antagonizes NMDA- and AMPA-induced seizure-like activity in planarians

Abstract

The mechanism of anticonvulsant action of topiramate includes inhibition of glutamate-activated ion channels. The evidence is most convincing for direct inhibitory action at the ionotropic AMPA (α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate ((2 S,3 S,4 S)-3-(Carboxymethyl)-4-prop-1-en-2-ylpyrrolidine-2-carboxylic acid) glutamate receptor subtypes. Less direct connection has been made to the NMDA ( N-Methyl- d-aspartate) subtype. In the present study, we demonstrate that NMDA and AMPA produce concentration-dependent seizure-like activity in planarians, a type of flatworm which possesses mammalian-like neurotransmitters. In contrast, planarians exposed to the inhibitory amino acid, glycine, did not display pSLA. For combination experiments, topiramate significantly reduced planarian seizure-like activity ( pSLA) produced by NMDA or AMPA. Additionally, NMDA-induced pSLA was antagonized by either an NMDA receptor antagonist (MK-801) or AMPA receptor antagonist (DNQX), thus suggesting that NMDA-induced pSLA was mediated by NMDA and non-NMDA receptors. The present results provide pharmacologic evidence of a functional inhibitory action of topiramate on glutamate receptor activity in invertebrates and provide a sensitive, quantifiable end-point for studying anti-seizure pharmacology.