title: Analysis of the action of gymnodimine-A and 13-desmethyl spirolide C on the mouse neuromuscular system in vivo.
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.
authors: CNRS, Centre de Recherche de Gif - FRC3115, Institut de Neurobiologie Alfred Fessard - FRC2118, Laboratoire de Neurobiologie et Développement - UPR3294, CNRS Bat. 32-33, 91198 Gif sur Yvette Cedex, France; Laboratoire de Toxines Alimentaires, Institut Pasteur de Tunis, 13 Place Pasteur, B.P. 74, 1002 Tunis-Belvédère, Tunisia.
authors: Riadh
authors: R
authors: Marrouchi
authors: Guillaume
authors: G
authors: Rome
authors: Riadh
authors: R
authors: Kharrat
authors: Jordi
authors: J
authors: Molgó
authors: Evelyne
authors: E
authors: Benoit
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004141:Dinoflagellida / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000633:toxicity*; D006844:Hydrocarbons, Cyclic / Q000633:toxicity*; D007097:Imines / Q000633:toxicity*; D008387:Marine Toxins / Q000633:toxicity*; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects; D009465:Neuromuscular Agents / Q000633:toxicity*; D009469:Neuromuscular Junction / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013141:Spiro Compounds / Q000633:toxicity*
chemical_list: C517170:13-desmethylspirolide C; D006575:Heterocyclic Compounds, 3-Ring; D006844:Hydrocarbons, Cyclic; D007097:Imines; D008387:Marine Toxins; D009465:Neuromuscular Agents; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; C407350:gymnodimine
keywords: 13-Desmethyl spirolide C; Cyclic imine toxins; Gymnodimine-A; In vivo studies; Mouse neuromuscular excitability; Nicotinic acetylcholine receptors