title: 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 (alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate ((2S,3S,4S)-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.
authors.affiliation: Department of Pharmaceutical Sciences and Pharmacology, Temple University School of Pharmacy and Medicine, Philadelphia, PA 19140, United States. scott.rawls@temple.edu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
authors.forename: Timmy
authors.initials: T
authors.lastname: Thomas
authors.forename: Mobilaji
authors.initials: M
authors.lastname: Adeola
authors.forename: Tanvi
authors.initials: T
authors.lastname: Patil
authors.forename: Natalie
authors.initials: N
authors.lastname: Raymondi
authors.forename: Asha
authors.initials: A
authors.lastname: Poles
authors.forename: Michael
authors.initials: M
authors.lastname: Loo
authors.forename: Robert B
authors.initials: RB
authors.lastname: Raffa
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D016202:N-Methylaspartate; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010932:Planarians / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control*; D000077236:Topiramate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011810:Quinoxalines; D000077236:Topiramate; D005632:Fructose; C056723:FG 9041; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid