Transcriptomic Analysis of Ciguatoxin-Induced Changes in Gene Expression in Primary Cultures of Mice Cortical Neurons, 2018, Rubiolo et al

Hutan · Jan 31, 2021

I've been interested in ciguatera for a while, because exposure to the ciguatoxin can cause long term symptoms that have a lot of similarities with those of ME/CFS. And also because early on in my illness I saw a paper by a Japanese researcher that found similarities in protein expression, I think it was, between ciguatera and ME/CFS patients.

This 2018 paper is interesting because the researchers found upregulated Ephrin genes, as Maureen Hansen's group has just found in ME/CFS patients.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983248/

Abstract

Ciguatoxins are polyether marine toxins that act as sodium channel activators. These toxins cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents several symptoms in humans including long-term neurological alterations.

Earlier work has shown that both acute and chronic exposure of primary cortical neurons to synthetic ciguatoxin CTX3C have profound impacts on neuronal function. Thus, the present work aimed to identify relevant neuronal genes and metabolic pathways that could be altered by ciguatoxin exposure.

To study the effect of ciguatoxins in primary neurons in culture, we performed a transcriptomic analysis using whole mouse genome microarrays, for primary cortical neurons exposed during 6, 24, or 72 h in culture to CTX3C. Here, we have shown that the effects of the toxin on gene expression differ with the exposure time.

The results presented here have identified several relevant genes and pathways related to the effect of ciguatoxins on neurons and may assist in future research or even treatment of ciguatera.

Moreover, we demonstrated that the effects of the toxin on gene expression were exclusively consequential of its action as a voltage-gated sodium channel activator, since all the effects of CTX3C were avoided by preincubation of the neurons with the sodium channel blocker tetrodotoxin.
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Andy · Jan 30, 2021

Hutan said: ↑

ciguatera and ME/CFS
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?

Chronic phase lipids in sera of chronic fatigue syndrome (CFS), chronic ciguatera fish poisoning (CCFP), hepatitis B, and cancer with antigenic epitope resembling ciguatoxin, as assessed with MAb‐CTX
https://onlinelibrary.wiley.com/doi/abs/10.1002/jcla.10079

Hutan · Jan 30, 2021

From this 2018 study
Background on ciguatera:

Ciguatoxins are polyether marine toxins known to activate voltage-gated sodium channels [1,2] and cause one of the most widespread forms of nonbacterial food poisoning, named ciguatera. Ciguatera fish poisoning is a seafood-borne illness caused by the consumption of fish contaminated with ciguatera toxins, produced by marine dinoflagellates of the genus Gambierdiscus.
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Long-term symptoms with similarities to ME/CFS (there are other accounts of symptoms that sound very similar indeed):

Among other symptoms, in humans, ciguatera fish poisoning is characterized by neurological alterations that may last for several months or even years, including paraesthesia, headache, weakness, cold allodynia, and sensory abnormalities such as pruritus, arthralgia, myalgia, and dental pain
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They think they have identified a mechanism for 'long-lasting neurological changes':

In the search for the cellular mechanisms underlying the long-lasting neurological changes produced by ciguatoxins in neurons, we have described that acute exposure of cortical neurons to the synthetic ciguatoxin CTX3C caused a rapid membrane depolarization and increased the amplitude of miniature inhibitory postsynaptic currents (mIPSCs), whereas it decreased the amplitude of miniature excitatory postsynaptic currents (mEPSCs).
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On the other hand, after 24 h exposure of cortical neurons to CTX3C, the toxin induced synaptic scaling, and its effects, besides the well-known shift in sodium channel activation to more negative voltages and membrane potential depolarization, included a decrease in neuronal firing activity and an increased frequency, but decreased amplitude of mEPSCs, which was linked to a reduced expression of N-methyl-d-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits and prevented by the voltage-gated sodium channel blocker tetrodotoxin (TTX) [17].
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All these results indicate that the rapid effects induced by ciguatoxins in neurons may have long-lasting neurological effects on brain function.
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On upregulated ephrins and axon guidance:

At 24 h, five of the upregulated genes were involved in axon guidance, specifically the semaphorin 6 and 4 genes, that participate in nervous system development and the Ephrin (Eph) receptors B and A5 genes. The Eph family of molecules comprises the largest group of receptor tyrosine kinases. These molecules have been shown to play important roles in many physiological functions including tissue segmentation, angiogenesis, axon guidance, and neural plasticity
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Hutan · Jan 30, 2021

Andy said: ↑

Chronic phase lipids in sera of chronic fatigue syndrome (CFS), chronic ciguatera fish poisoning (CCFP), hepatitis B, and cancer with antigenic epitope resembling ciguatoxin, as assessed with MAb‐CTX
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Good try, but I don't think that was the paper I was thinking of. I'll try to find it.

Mithriel · Jan 30, 2021

From memory, a researcher from the University of Hawaii worked on this but also the NIH or someplace like that. One of the problems was he called it ciguatera while the other papers spoke about anticardiolipin.

It was very exciting work but just seemed to fade away. When the doctor died no one took it up.

Another lost opportunity to either confirm something or prove it false.

Dolphin · Jan 30, 2021

Mithriel said: ↑

From memory, a researcher from the University of Hawaii worked on this but also the NIH or someplace like that. One of the problems was he called it ciguatera while the other papers spoke about anticardiolipin.

It was very exciting work but just seemed to fade away. When the doctor died no one took it up.

Another lost opportunity to either confirm something or prove it false.
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The National CFIDS Foundation website might be a good place to look for information on this as they were interested in this angle.

Hutan · Jan 31, 2021

@Snow Leopard, have you seen this? In your cornucopia of papers, you seem to be focusing on some of the molecules and processes that are thought to be important in long term ciguatera. There are quite a lot of recent papers on the pathology of ciguatera, as, with climate change, it seems to becoming more of a risk to the people with the funds to investigate things.

To me, it seems quite important that here is a somewhat understood pathology that causes symptoms very like ME/CFS - chronic, relapsing. Alcohol seems to exacerbate symptoms; the development of a range of food allergies (not just to foods containing low levels of the ciguatoxin) seems quite common.

Snow Leopard · Jan 31, 2021

Hutan said: ↑

@Snow Leopard, have you seen this? In your cornucopia of papers, you seem to be focusing on some of the molecules and processes that are thought to be important in long term ciguatera. There are quite a lot of recent papers on the pathology of ciguatera, as, with climate change, it seems to becoming more of a risk to the people with the funds to investigate things.
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The common patterns between ciguatera and ME are interesting, multiple underlying causes with commonalities in the end point.

The study (in the OP) is less compelling because it is based on cell culture of mice neurons, rather than human patients and I am interested in the interactions on a physiological scale (where the microenvironment is of utmost importance), which doesn't really translate well from cell culture.

Also, the link to the actual study which is missing from the OP: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983248/

Hutan · Jan 31, 2021

Thanks Snow Leopard, link added. Here's a recent overview of studies of the pathology, some in humans.
Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis, 2020, L'Herondelle et al

Hutan · Apr 29, 2023

From an information sheet about Ciguatera
https://www.whoi.edu/science/B/redtide/illness/ciguatera_fish_poisoning.html

Molecular Mechanism of Action:

The two most common toxins associated with Ciguatera are Ciguatoxin and Maitotoxin, and they are some of the most lethal natural substances known. In mice, ciguatoxin is lethal at 0.45 ug/kg ip, and maitotoxin at a dose of 0.15 ug/kg ip. Oral intake of as little as 0.1 ug ciguatoxin can cause illness in the human adult (as an extrapolation from fish samples eaten).

Ciguatoxin, a lipid soluble substance, opens voltage dependant sodium channels in cell membranes which induces membrane depolarization. It causes prolonged symptoms indicate nerve blockage or damage requiring regeneration of nervous tissue Maitotoxin, water soluble, specifically increases the calcium ion influx through excitable membrane; this is not affected by tetrodotoxin or sodium. Usually Maitotoxin is less important since it is less present in fish. Scaritoxin is similar to Ciguatoxin. Okadaic Acid is a lipid soluble toxin with a LD50 210 ug/kg ip in mice; it is a sodium ionophore. Palytoxin is a water soluble polyether which causes severe tonic contraction of all muscle groups; it also strong skin irritant and potent tumor activator.

The pharmacologic action of Ciguatoxin is due to its direct effects on excitable membranes. Its potent depolarizing action due to a selective increases in sodium permeability in the nerve cells and striated muscle can be counteracted by calcium ions and tetrodotoxin. The respiratory arrest induced by a lethal dose results mainly from depression of the central respiratory center. It causes biphasic cardiovascular response with hypotension and bradycardia (which can be antagonized with anticholinergics) followed by hypertension and tachycardia (which can be suppressed by adrenergic blockers). The response of smooth muscle to ciguatoxin is complex, depending upon the predominant autonomic innervation and postsynaptic receptor. It causes a potent release of endogenous norepinephrine from adrenergic nerve terminals and a potentiating effect on the post synaptic membrane.

Maitotoxin possesses a specific Ca2+ dependent action which causes a release of norepinephrine from rat pheochromocytoma cells. This action occurs in the absence of Na+ ions and in the presence of tetrodotoxin, precluding the participation of sodium channels; Maitotoxin appears to exert its effects on endogenous membrane calcium channels.
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One of the toxins present in varying amounts in Ciguatera fish poisoning, that we haven't discussed before is maitotoxin. It increases calcium ion influx through excitable membranes; it seems to work on calcium channels, including possibly TRP channels.

In Polynesia, Ciguatera is dominated and initiated by neurologic symptoms (90% of patients report paresthesias and dysesthesia), while reports from the Caribbean suggest that Ciguatera initially presents acutely as a gastroenteritis often with associated cardiovascular symptoms, with the gradual onset and dominance of neurologic symptoms over the first 24 hours. This may be due to different toxins mixtures elaborated by Caribbean and Polynesian G. toxicus.
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The symptoms of Ciguatera poisoning, especially the paresthesias and weakness, can persist in varying severity for weeks to months after the acute illness. Prolonged itching due to chronic Ciguatera can present as a dermatologic disease when it is really due to ciguatera paresthesias. Chronic ciguatera can also present as a psychiatric disorder of general malaise, depression, headaches, muscular aches, and peculiar feelings in extremities for several weeks. It is reported that those with chronic symptoms seem to have recurrences of their symptoms with the ingestion of fish (regardless of type), ethanol, caffeine, and nuts 3 to 6 months from initial ingestion.
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Amitriptyline (25 to 75 mg bid) and similar medications do seem to have some success in relieving the symptoms of chronic Ciguatera, such as fatigue and paresthesias. It is possible that nifedipine may be appropriate as a calcium channel blocker to counteract the effects of maitotoxin. Finally, there are over 64 different local remedies including medicinal teas used in both the Indo-Pacific and West Indies regions. None of these treatments have been evaluated in a controlled clinical trial with the exception of two controlled trials of Mannitol for treatment of acute Ciguatera, so that their true efficacy is impossible to determine.
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With apparent considerable success, at least acutely, mannitol infusions have been used. Palafox et al (1988) administered 1 gm/kg of 20% mannitol at a rate of 500 mL/h "piggybacked" to an iv infusion of 5% dextrose in Ringers lactate or saline solution at 30 mL/h or more depending on fluid requirements with complete reversal of symptoms in the majority of patients tested. Subsequent reports have affirmed his success although mannitol appears to be most effective in completely relieving symptoms when given within the first 48-72 hours from ingestion.
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