Pinnatoxins, an emergent class of marine toxins interacting with nAChRs. Pharmacological characterization, biodistribution and musculo-skeletal effect of these neurotoxic agents
Résumé
Cyclic imines produced by marine dinoflagellate microorganisms, constitute a widely distributed group of phycotoxins with increasing prevalence in oceanic environment due to recent climate change. During active dinoflagellate blooms, phycotoxins may accumulate in shellfish tissues and can be transferred into fish, marine mammals and ultimately to humans. Among these phycotoxins, pinnatoxins (PnTx-A to H), produced by the dinoflagellate Vulcanodinium rugosum, were recently identified and shown to exhibit the highest oral acute mouse toxicity among cyclic imine toxins. We will describe binding and electrophysiological experiments highlighting the exceptional ability of these toxins to interact with various subtypes of nicotinic receptors (nAChRs), especially the muscle and neuronal (α7) subtypes. Biodistribution analyses by digital radioimaging in rats, after oral or i.v administration of tritiated PnTx-G, revealed the presence of the toxin in various peripheral organs, as well as in the central nervous system, highlighting its property to cross both the intestinal and the blood-brain barriers. Moreover, using the chick embryo as a first model, we show that during embryonic development, PnTx-A exposure reduces embryo motility by decreasing the embryo spontaneous movements which affected the maturation of the musculoskeletal system.