title: Isodomoic acids A and C exhibit low KA receptor affinity and reduced in vitro potency relative to domoic acid in region CA1 of rat hippocampus.
abstract: Several natural isomers of the seizurogenic neurotoxin domoic acid (DA) have been found to occur at up to mg/kg levels in shellfish. The aim of the current study was to assess the neurotoxic potency of isodomoic acids A and C (Iso-A and Iso-C), recently isolated from commercial shellfish. Hippocampal slices were obtained from young adult rats and maintained in a tissue recording chamber. Synaptically evoked population spikes were recorded in region CA1 before and after exposure to DA or its isomers. Both Iso-A and Iso-C produced transient neuronal hyperexcitability followed by a dose-dependent suppression of population spikes, but were, respectively, 4- and 20-fold less potent than DA (spike area: EC50 DA=237 nM; Iso-A=939 nM; Iso-C=4.6 microM). In the hippocampus, DA preconditioning induces tolerance to subsequent DA toxicity. However, in the present study neither Iso-A nor Iso-C were effective as preconditioning agents. Competitive binding studies using homomeric GluR6 kainate (kainic acid, KA) receptors showed the affinity of Iso-A to be 40-fold lower than DA (Ki DA=3.35 nM; Iso-A=130 nM). Together with earlier work showing Iso-C affinity at GluR6 receptors to be 240-fold lower than DA, our results suggest that neuroexcitatory effects of Iso-A in CA1 may involve both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and KA receptors, while Iso-C likely involves the activation of AMPA receptors alone.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago School of Medical Sciences, P.O. Box 913, Dunedin, New Zealand.
authors.forename: P M
authors.initials: PM
authors.lastname: Sawant
authors.forename: B A
authors.initials: BA
authors.lastname: Weare
authors.forename: P T
authors.initials: PT
authors.lastname: Holland
authors.forename: A I
authors.initials: AI
authors.lastname: Selwood
authors.forename: K L
authors.initials: KL
authors.lastname: King
authors.forename: C M
authors.initials: CM
authors.lastname: Mikulski
authors.forename: G J
authors.initials: GJ
authors.lastname: Doucette
authors.forename: D O
authors.initials: DO
authors.lastname: Mountfort
authors.forename: D S
authors.initials: DS
authors.lastname: Kerr
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D006538:Heptanoic Acids / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007536:Isomerism; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008387:Marine Toxins / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000378:metabolism*
chemical_list: D006538:Heptanoic Acids; D007608:Kainic Acid; D008387:Marine Toxins; D009498:Neurotoxins; D018092:Kainic Acid Receptors; C524833:isodomoic acid A; C504322:isodomoic acid C; C012301:domoic acid