Synthetic Pinnatoxins A and G Reversibly Block Mouse Skeletal Neuromuscular Transmission In Vivo and In Vitro

Benoit, Évelyne; Couesnon, Aurélie; Lindovský, Jiří; Iorga, Bogdan I.; Aráoz, Rómulo; Servent, Denis; Zakarian, Armen; Molgó, Jordi

doi:10.3390/md17050306

Cited by 13 publications

(13 citation statements)

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“…At the dose of 220 µg kg −1 and above, PnTx-G induced lethal effects within 30 minutes after its administration. Before death, mice showed piloerection, prostration, hypothermia, abdominal breathing, paralysis of the hind limbs, and cyanosis, consistent with nicotinic receptors blocking action by PnTx-G [23][24][25][26][27][28][29][30]. No signs of toxicity were recorded in survived mice.…”

Section: Discussionmentioning

confidence: 60%

“…No significant changes in serum markers of liver, kidney, and/or muscle damage (AST, ALT, GLDH, creatinine, CPK) or of selected ions (Na + , K + , Ca 2+ , Cl − , P i ) as indices of electrolytes homeostasis have been recorded. The absence of significant morphological tissues alterations in the main organs could be related to a fast functional damage induced by the toxin, such as neuromuscular block consequent to the antagonistic effect on nicotinic acetylcholine receptors [23][24][25][26][27][28][29][30], rather than a structural tissue damage. On the other hand, the nicotinic receptors antagonism might be at the basis of the main neuromuscular signs of mice before death (prostration, respiratory depression and hind limbs paralysis).…”

Section: Discussionmentioning

confidence: 99%

“…The toxicity is ascribed mainly to a specific interaction and blockage of muscle-and neuronal-type nicotinic acetylcholine receptors, known to be involved in synaptic transmissions at central and peripheral nervous system as well as at skeletal neuromuscular junction level. In particular, PnTXs bind muscle nicotinic acetylcholine receptors more potently than neuronal ones [23][24][25][26][27][28][29][30]. Intraperitoneal injection of these toxins in mice has been shown to induce skeletal muscle paralysis, respiratory depression, and lethal effects within less than one hour.…”

Section: Introductionmentioning

confidence: 99%

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Acute Oral Toxicity of Pinnatoxin G in Mice

Sosa

Pelin

Cavion

et al. 2020

Toxins

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Pinnatoxin G (PnTx-G) is a marine cyclic imine toxin produced by the dinoflagellate Vulcanodinium rugosum, frequently detected in edible shellfish from Ingril Lagoon (France). As other pinnatoxins, to date, no human poisonings ascribed to consumption of PnTx-G contaminated seafood have been reported, despite its potent antagonism at nicotinic acetylcholine receptors and its high and fast-acting toxicity after intraperitoneal or oral administration in mice. The hazard characterization of PnTx-G by oral exposure is limited to a single acute toxicity study recording lethality and clinical signs in non-fasted mice treated by gavage or through voluntary food ingestion, which showed differences in PnTx-G toxic potency. Thus, an acute toxicity study was carried out using 3 h-fasted CD-1 female mice, administered by gavage with PnTx-G (8–450 µg kg−1). At the dose of 220 µg kg−1 and above, the toxin induced a rapid onset of clinical signs (piloerection, prostration, hypothermia, abdominal breathing, paralysis of the hind limbs, and cyanosis), leading to the death of mice within 30 min. Except for moderate mucosal degeneration in the small intestine recorded at doses of 300 µg kg−1, the toxin did not induce significant morphological changes in the other main organs and tissues, or alterations in blood chemistry parameters. This acute oral toxicity study allowed to calculate an oral LD50 for PnTx-G equal to 208 μg kg−1 (95% confidence limits: 155–281 µg kg−1) and to estimate a provisional NOEL of 120 µg kg−1.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute Oral Toxicity of Pinnatoxin G in Mice

Sosa

Pelin

Cavion

et al. 2020

Toxins

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“…Gymnodimines (GYMs), spirolides (SPXs), pinnatoxins (PnTXs), pteriatoxins (PtTXs), prorocentrolides, spiro-prorocentrimine, portimines, and symbioimines belong to cyclic imines (CIs), a family of marine biotoxins produced by dinoflagellates and accumulated in shellfish [1][2][3]. These compounds share as a common structural motif an imine group in a cyclic moiety, which has been identified as a pharmacophore with biological activity [4,5]. CIs have a mode of action based on the inhibition of nicotinic acetylcholine receptors, and although neurotoxic effects were observed in toxicological assays, as of yet there has been no reported information about human intoxication linked to their assimilation [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Cyclic Imines in Mussels (Mytilus galloprovincialis) from Galicia (NW Spain) by LC-MS/MS

Moreiras

Leão

Gago-Martı́nez

2019

IJERPH

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Cyclic imines (CIs) are being considered as emerging toxins in the European Union, and a scientific opinion has been published by the European Food Safety Authority (EFSA) in which an assessment of the risks to human health related to their consumption has been carried out. Recommendations on the EFSA opinion include the search for data occurrence of CIs in shellfish and using confirmatory methods by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which need to be developed and optimized. The aim of this work is the application of LC-MS/MS to the analysis of gymnodimines (GYMs), spirolides (SPXs), pinnatoxins (PnTXs), and pteriatoxins (PtTXs) in mussels from Galician Rias, northwest Spain, the main production area in Europe, and therefore a representative emplacement for their evaluation. Conditions were adjusted using commercially available certified reference standards of GYM-A, SPX-1, and PnTX-G and evaluated through quality control studies. The EU-Harmonised Standard Operating Procedure for determination of lipophilic marine biotoxins in molluscs by LC-MS/MS was followed, and the results obtained from the analysis of eighteen samples from three different locations that showed the presence of PnTXs and SPXs are presented and discussed. Concentrations of PnTX-G and SPX-1 ranged from 1.8 to 3.1 µg/kg and 1.2 to 6.9 µg/kg, respectively, and PnTX-A was detected in the group of samples with higher levels of PnTX-G after a solid phase extraction (SPE) step used for the concentration of extracts.

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“…The potent neurotoxicity of PnTXs and associated symptoms led authors to investigate their effects on skeletal muscle contraction. A recent study clearly shows that synthetic PnTX-A and -G, when injected in vivo in the mouse tail muscle at nanomolar concentrations (nmol of PnTX per kg of mouse), caused a dose- and time-dependent reduction of the nerve-evoked compound muscle action potential (CMAP), which reflects the number of muscle fibers that are able to trigger an action potential upon nerve stimulation [15]. The block of neuromuscular transmission in vivo by PnTX-A and -G is reversible in 6 to 8 h.…”

Section: Acute Toxicitymentioning

confidence: 99%

Pinnatoxins’ Deleterious Effects on Cholinergic Networks: From Experimental Models to Human Health

Delcourt¹,

Lagrange

Abadie

et al. 2019

Marine Drugs

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Pinnatoxins (PnTXs) are emerging neurotoxins that were discovered about 30 years ago. They are solely produced by the marine dinoflagellate Vulcanodinium rugosum, and may be transferred into the food chain, as they have been found in various marine invertebrates, including bivalves. No human intoxication has been reported to date although acute toxicity was induced by PnTxs in rodents. LD50 values have been estimated for the different PnTXs through the oral route. At sublethal doses, all symptoms are reversible, and no neurological sequelae are visible. These symptoms are consistent with impairment of central and peripheral cholinergic network functions. In fact, PnTXs are high-affinity competitive antagonists of nicotinic acetylcholine receptors (nAChRs). Moreover, their lethal effects are consistent with the inhibition of muscle nAChRs, inducing respiratory distress and paralysis. Human intoxication by ingestion of PnTXs could result in various symptoms observed in episodes of poisoning with natural nAChR antagonists. This review updates the available data on PnTX toxicity with a focus on their mode of action on cholinergic networks and suggests the effects that could be extrapolated on human physiology.

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Synthetic Pinnatoxins A and G Reversibly Block Mouse Skeletal Neuromuscular Transmission In Vivo and In Vitro

Cited by 13 publications

References 50 publications

Acute Oral Toxicity of Pinnatoxin G in Mice

Acute Oral Toxicity of Pinnatoxin G in Mice

Analysis of Cyclic Imines in Mussels (Mytilus galloprovincialis) from Galicia (NW Spain) by LC-MS/MS

Pinnatoxins’ Deleterious Effects on Cholinergic Networks: From Experimental Models to Human Health

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