Topiramate antagonizes NMDA- and AMPA-induced seizure-like activity in planarians.
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.
Rawls
Scott M
SM
Department of Pharmaceutical Sciences and Pharmacology, Temple University School of Pharmacy and Medicine, Philadelphia, PA 19140, United States. scott.rawls@temple.edu
Thomas
Timmy
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Adeola
Mobilaji
M
Patil
Tanvi
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Raymondi
Natalie
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Poles
Asha
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Loo
Michael
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Raffa
Robert B
RB
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
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