The genus Gambierdiscus can synthesize at least two major families of toxins: one lipid-soluble, the Ciguatoxins (CTXs) and another water-soluble, the Maitotoxins (MTXs). It is generally agreed that only CTXs are responsible for ciguatera fish poisoning, MTXs are usually not involved in human poisonings.

In humans, the average dose at which 50% of humans develop the symptoms, is estimated to be as low as 2 ng/kg of body weight, making CTXs one of the most potent natural substances known.

Other molecules such as gambieric acids, which exhibit antifungal activity, and gambierol have also been isolated from cultures of this micro-algae, but their role in ciguatera poisoning is still to be confirmed.

One might wonder about the ecological benefit for Gambierdiscus to produce these toxins. One hypothesis is that these metabolites provide an environmental benefit (e.g. defense mechanism) over potential competitors or predators.

THE CIGUATOXINS

Ciguatoxins (CTXs) are polycyclic polyether compounds, lipid-soluble, with a molecular weight between 1.023 and 1.159 Da. There are 3 main groups of CTXs throughout the main areas affected by ciguatera: Pacific ciguatoxins or P-CTXs, Caribbean ciguatoxins or C-CTXs and Indian Ocean ciguatoxins or I-CTXs. P-CTXs, composed of 13 ether rings, are described in two types, 1 and 2, the difference residing mainly in the E cycle. C-CTXs are composed of 14 cyclic ethers. To date, the structure of I-CTXs is yet to discover. In total, there are more than 40 different CTXs, which have been isolated primarily from Gambierdiscus cells and contaminated organisms.

The panel of CTXs in contaminated fish can vary significantly from one fish species to another. One single species may host several types of CTXs. So, one may talk about a “toxic profile” for a given trophic level.

Algal CTXs produced by Gambierdiscus undergo transformations from their accumulation in herbivorous fish until they pass through carnivorous fish. As a result, CTXs polarity as well as their toxicity increase. Thus, P-CTX-1B only found in carnivorous fish is 30 times more toxic than P-CTX-4B present in Gambierdiscus. This biotransformation phenomenon is responsible for the wide variability of the toxic profiles with respect to the fish and trophic level considered.

These understandings partly illustrate the complex mechanisms underlying the significant variation of ciguatera outbreaks severity from a geographical region to another.

Ciguatoxin P-CTX1B (extracted from carnivorous)

MODE OF ACTION

Impaired Nerve Conduction

A well-known consequence of the binding of CTXs to Nav channels, which they maintain in a permanent open state, is the appearance of spontaneous and/or repetitive discharges of action potentials. The marked increase of cellular excitability, generated by the binding of CTXs, in turn activates a sustained release of neurotransmitters (until exhaustion) at the level of the nerve endings, thus causing a modification of synaptic efficiency or even a deficiency in nerve messages transmission.

Modification of Cells Morphology

As a consequence of a massive influx of Na+ ions into the cells, following the binding of CTXs, a significant increase in the volume of the nodes of Ranvier of myelinated nerve fibers and synaptic terminals is observed, resulting from a call of compensatory water molecules, from the extracellular compartment to the intracellular compartment.

All of the modifications induced by CTXs (depolarization and hyper-excitability, increase in intracellular Na+ and Ca2+, anarchic release of neuromediators, swelling linked to the influx of water, etc.), associated with the very broad distribution of their biological targets within the organism, is at the origin of the diversity of the clinical signs observed in the CP-affected persons.

Thus, at neurological level, the multitude of symptoms encountered in CP such as motor, sensory, cerebellar, psychiatric impairments, is a direct consequence of the alteration of the fibers of the peripheral, central and autonomic nervous system. At digestive level, it is the high level of intracellular Ca2+ that would be the cause of profuse diarrhea. At the cardiac level, the action of CTXs takes place via the autonomic nervous system, with bradycardia and hypotension being linked to parasympathetic hyperstimulation and low sympathetic tone. Finally, at muscle level, the intracellular increase in Ca2+ generates an increase in the frequency and intensity of muscle contractions, while the discharges of spontaneous and repetitive action potentials induce disordered muscle contractions. These effects are all the more important when they concern the heart muscle since it is both the nerves supplying the heart and the heart muscle that are affected.

Sites and modes of action of ciguatoxins. (A) In motor and sensory neurons ciguatoxins cause persistent activation of Nav channels (1) and block Kv channels (2). This causes both membrane depolarisation (3) and leads to spontaneous and repetitive action potential firing (4). The resultant Na+ loading causes swelling of axons, nerve terminals and perisynaptic Schwann cells (5). (B) At synapses, ciguatoxins elevate the intracellular Ca2+ concentration via InsP3-mediated Ca2+ release from internal stores (6) or via activation of Cav channels due to terminal depolarisation (8). Also intracellular concentrations of Ca2+ increase due to an alteration in the Na+ gradient driving the Na+-Ca2+ exchanger (7), an effect that also occurs in cardiac myocytes. The tonic action potential firing initiated in axons induces repetitive, synchronous and asynchronous neurotransmitter release at synapses and the neuromuscular junction (9), to produce transient increases and decreases in the quantal content of synaptic responses. This results in spontaneous and tetanic muscle contractions (10). In addition, ciguatoxins also impair synaptic vesicle recycling that exhausts the pool of neurotransmitter vesicle available for release. By Nicholson et Lewis, 2006

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