Neuromuscular blocking activity of pinnatoxins E, F and G

• Published in: Toxicon (Oxford) Vol. 76; pp. 214 - 220
• Main Authors: Hellyer, Shane D., Selwood, Andrew I., Rhodes, Lesley, Kerr, D. Steven
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-12-2013
• Subjects: Alkaloids - toxicity; Animals; antagonists; Bioassay; bioassays; Biocompatibility; Biomedical materials; cholinergic receptors; death; Dinophyceae; Electrophysiological Phenomena; Electrophysiology; evoked potentials; Harmful algal toxins; Imines; In Vitro Techniques; inhibitory concentration 50; isomers; Male; mechanism of action; membrane potential; muscle fibers; Muscles; nerve tissue; Neuromuscular block; Neuromuscular Blocking Agents - toxicity; Neuromuscular Junction - drug effects; Pinnatoxin; Rats; Rats, Sprague-Dawley; Receptors; Spiro Compounds - toxicity; Surgical implants; Toxicity; Toxins; Electrophysiology; Pinnatoxin; Neuromuscular block; Harmful algal toxins
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2013.10.009

Pinnatoxins are produced by dinoflagellates and belong to the cyclic imine family of toxins. They are fast-acting and highly toxic when administered in vivo in rodent bioassays, causing death by respiratory depression within minutes. Studies have revealed that some cyclic imine toxins cause their toxicity by antagonizing both muscle type and heteromeric and homomeric neuronal nicotinic acetylcholine receptors (nAChRs). Pinnatoxins E, F and G all display potent toxicity in in vivo bioassays, with symptoms of toxicity similar to other cyclic imine toxins. However, very little work has been done on the mechanism of action of these pinnatoxin isomers. Thus the aim of the current study was to investigate the rank order of potency and mechanism of action of pinnatoxins E, F and G. The effects of pinnatoxin E, F and G on in vitro rat hemidiaphragm preparations were investigated using twitch tension and electrophysiological techniques to determine the effects of these toxins on cholinergic transmission at the neuromuscular junction. Pinnatoxins E, F and G all produced concentration-dependent reductions in the nerve evoked twitch response of the rat hemidiaphragm, with IC50 values ranging from 11 to 53 nM and a rank order of potency of F > G > E. Only complete washout of pinnatoxin E was evident, with pinnatoxins F and G displaying slow and incomplete washout profiles. Pinnatoxins F and G also reduced the amplitudes of spontaneous miniature endplate potentials and evoked endplate potentials at the neuromuscular junction, without affecting miniature endplate potential frequency or the resting membrane potential of the muscle fibres. These results show that pinnatoxins E, F and G are all potent neuromuscular blocking agents and cause toxicity by acting as antagonists at muscle type nicotinic acetylcholine receptors.
•We examined pinnatoxins E, F and G in rat hemidiaphragm.•Pinnatoxins E, F and G reduced nerve evoked twitch responses (IC50 11–53 nM).•Pinnatoxins F and G reduced spontaneous and evoked endplate potentials.•Pinnatoxins F and G did not affect mEPP frequency or resting membrane potential.