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Analysis of the action of gymnodimine-A and 13-desmethyl spirolide C on the mouse neuromuscular system in vivo.
- Source :
-
Toxicon : official journal of the International Society on Toxinology [Toxicon] 2013 Dec 01; Vol. 75, pp. 27-34. Date of Electronic Publication: 2013 Aug 15. - Publication Year :
- 2013
-
Abstract
- Gymnodimine-A and 13-desmethyl spirolide C are marine toxins belonging to the cyclic imine group produced by Karenia selliformis and Alexandrium ostenfeldii/peruvianum dinoflagellates, respectively. The aim of this work was to analyze the pharmacological properties of both toxins (at sub-lethal doses) on neuromuscular excitability, when injected locally to isoflurane-anesthetized mice, using a multimodal minimally-invasive in vivo electrophysiological approach. The main effect of both toxins was a marked reversible time- and dose-dependent decrease of the compound muscle action potential recorded from the tail muscle in response to caudal motor nerve stimulation. The dose-response curves of gymnodimine-A and 13-desmethyl spirolide C effect on the maximal amplitude of compound muscle action potential revealed 50% inhibitory doses of 51 ng/mouse (i.e. 1.6 μg/kg or 3.3 nmol/kg mouse) and 0.18 ng/mouse (i.e. 6 ng/kg or 0.01 nmol/kg mouse), respectively. The blocking effect occurred without significant modification of motor nerve excitability parameters. It is concluded that the inhibition of the mouse compound muscle action potential, induced by gymnodimine-A and 13-desmethyl spirolide C, results from an action of these toxins at the level of the skeletal neuromuscular junction, since both cyclic imine toxins are known to interact and block muscle-type nicotinic acetylcholine receptors. In the present in vivo study, 13-desmethyl spirolide C was about 300 fold more active than gymnodimine-A on equimolar basis. The present in vivo approach, associated to recent progress in chemical synthesis of cyclic imine toxins, paves the way for more detailed structure-activity studies to obtain new and more potent synthetic analogs.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- Action Potentials drug effects
Animals
Dinoflagellida metabolism
Dose-Response Relationship, Drug
Electrophysiological Phenomena
Female
Mice
Motor Neurons drug effects
Muscle, Skeletal drug effects
Receptors, Nicotinic drug effects
Receptors, Nicotinic metabolism
Heterocyclic Compounds, 3-Ring toxicity
Hydrocarbons, Cyclic toxicity
Imines toxicity
Marine Toxins toxicity
Neuromuscular Agents toxicity
Neuromuscular Junction drug effects
Spiro Compounds toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3150
- Volume :
- 75
- Database :
- MEDLINE
- Journal :
- Toxicon : official journal of the International Society on Toxinology
- Publication Type :
- Academic Journal
- Accession number :
- 23954513
- Full Text :
- https://doi.org/10.1016/j.toxicon.2013.08.050