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

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. Hippocampa...

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Published in:	Toxicon (Oxford) Vol. 50; no. 5; pp. 627 - 638
Main Authors:	Sawant, P.M., Weare, B.A., Holland, P.T., Selwood, A.I., King, K.L., Mikulski, C.M., Doucette, G.J., Mountfort, D.O., Kerr, D.S.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-10-2007 Elsevier Science
Subjects:	Animals Binding, Competitive Biological and medical sciences Domoic acid Dose-Response Relationship, Drug Drug Tolerance Excitatory Postsynaptic Potentials - drug effects Excitatory Postsynaptic Potentials - physiology Heptanoic Acids - pharmacology Hippocampal slice Hippocampus - drug effects Hippocampus - metabolism In vitro preconditioning Isodomoic acid A Isodomoic acid C Isomerism KA receptor affinity Kainic Acid - analogs & derivatives Kainic Acid - pharmacology Male Marine Toxins - pharmacology Medical sciences Neurotoxins - pharmacology Organ Culture Techniques Plant poisons toxicology Rats Rats, Wistar Receptors, Kainic Acid - metabolism Toxicology Isodomoic acid A Hippocampal slice In vitro preconditioning KA receptor affinity Isodomoic acid C Domoic acid Rat Rodentia Central nervous system In vitro Phycotoxin Histological section Encephalon Vertebrata Mammalia Animal Affinity Hippocampus
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Summary:	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: EC 50 DA=237 nM; Iso-A=939 nM; Iso-C=4.6 μM). 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 ( K i 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and KA receptors, while Iso-C likely involves the activation of AMPA receptors alone.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0041-0101 1879-3150
DOI:	10.1016/j.toxicon.2007.05.010