How Ciguatoxins Cause CIRS, Brain Fog, & Loss of NAD+

How Ciguatoxins Cause CIRS, Brain Fog, & Loss of NAD+

 
ciguatoxin fish.jpg
 

Ciguatoxins are a harmful byproduct of marine life and their exposure can cause both acute and chronic long term neurological effects.

In this post, we will discuss how ciguatoxins can cause CIRS, brain fog, and loss of NAD+.

Contents:

  1. Ciguatoxin Basics

  2. How Are We Exposed to CTX?

  3. Why It’s Hard To Identify Fish Carrying CTX

  4. Symptoms From CTX Poisoning

  5. Other Downsides To CTX

  6. Chronic Ciguatera, Chronic Inflammatory Response Syndrome, and Systemic And Long-term Inflammation

  7. Ciguatoxin And Brain Fog

  8. Ciguatoxin And NAD+ Loss

  9. Testing

  10. What To Do About CTX

  11. What Makes CTX Worse?

  12. Mechanism Of Action

Ciguatoxin Basics

Ciguatoxin (CTX) is a fat soluble marine toxin that comes from the flagella Gambierdiscus spp and Fukuyoa spp., which grows near coral reefs. R R

Gambierdiscus also produces water-soluble maitotoxins, as well as gambieric acid, and gambierol, but has yet to be shown to play a role in Ciguatera Fish Poisoning (CFP). R

How Are We Exposed To CTX?

 
 https://link.springer.com/article/10.1007%2Fs12640-017-9780-3

https://link.springer.com/article/10.1007%2Fs12640-017-9780-3

 

Bioaccumulation

CTX bioaccumulate in marine animals and can be found in high levels in: R R

  • Amberjack (Carangidae, g. Seriola)

  • Barracuda (Sphyraenidae)

  • Grouper (Serranidae)

  • Hogfish (Labridae, g. Lachnolaimus)

  • Jacks (Carangidae)

  • Moray eel (Muraenidae)

  • Narrow barred mackerel (Scombridae, g. Scomberomorus)

  • Parrot fish (Scaridae)

  • Sea Urchins

  • Sharks R

  • Snapper (Lutjanidae)

  • Spanish mackerel (Scombridae, g. Scomberomorus)

  • Surgeon fish (Acanthuridae)

  • Trevally (Carangidae, g. Caranx)

  • Triggerfish (Balistidae)

  • Wrasses (Labridae)

The higher up in the food web, the higher chance of bioaccumulation and poisoning and the further down the chain, CTX may become more oxidized and may be more stressful to the liver. R R

Bioaccumulation of CTX has also reached herbivorous coral reef fish. R

Consumption of the fish head or organs (e.g., liver or gonads) is associated with greater symptom severity than eating only the fillet. R R

Gambierdiscus is found more commonly in the Pacific Ocean, Caribbean Sea, and Indian Ocean, but it has also been speculated that CTXs may accumulate in farm-raised fish that are fed wild fish contaminated with CTX. R R R R

Within the past 13 years, Gambierdiscus has been identified in the western Gulf of Mexico, eastern Mediterranean, Crete, Brazil, Hong Kong, Thailand, Europe, Australia, and West Africa (eastern Atlantic Ocean). R R R

Many eastern North American States also have had contaminated markets - for example, in Florida in 2013, for instance, certain species of Grouper, Snapper, Mackerel, and Jacks were among the top 20 types of fish sold, as well as barracuda (extremely high potential to be ciguatoxic). R

Harmful Algal Blooms

The increase of Carbon Dioxide (CO2) concentrations may also influence the abundance of Gambierdiscus by increasing the rate of Harmful Algal Blooms (HABs) - possibly causing ocean acidification and potential shifts in biological processes such as photosynthesis, nutrient uptake, growth, reproduction, community structure, and diversity of marine biota, R

Why It's Hard To Identify Fish Carrying CTX

The CTXs are tasteless, colorless, odorless, heat and acid stable, and stable for at least six months at commercial freezing temperatures. R

Also, CTX is not destroyed by cooking. R

New technologies may use yeast to identify CTX via Calcineurin signalling pathway. R

Symptoms From CTX Poisoning

Since CTX is lipophyilic (fat soluble), it is easily able to cross the Blood-Brain Barrier (BBB, get into the brain) and cause central and peripheral neurologic symptoms: R R R R

  • Anxiety

  • Arthralgia

  • Asthenia

  • Burning sensation (throat, mouth)

  • Cardiovascular symptoms

  • Cold allodynia

  • Depression

  • Diarrhea

  • Hallucinations

  • Headache, dizziness

  • Hypothermia, chills

  • Itching

  • Memory Loss

  • Myalgia

  • Nausea/vomiting

  • Pain (in general) R

  • Tingling

  • Tooth Pain

  • Touch disturbances

  • Urogenital discomfort/urogenital burning/urogenital pain

  • Vision disorder

More specific symptoms with frequency of clinical symptoms of CFP can be seen here.

Acute vs Chronic Symptoms

Gastrointestinal symptoms and signs usually begin within 6–12 h of fish consumption and resolve spontaneously within 1–4 days.

Neuropsychological symptoms can become apparent in the days or weeks after the initial or acute illness which can last for months or years. R R

Although rare, dehydration, cardiovascular shock, or (very rarely) respiratory failure resulting from paralysis of the respiratory musculature from CTX can result in death. R

Other Downsides To CTX

Other than the symptoms listed above, CTX may:

  • Act as hapten-binding stimulant R

  • Body Temperature Reversal R R R

  • Possible CIRS (see more in section below) R

  • Emotional/Cognitive dysfunctions - such as anxiety and impairment of spatial memory/decision-making R

  • Hypersensitivity to any inflammogens - such as multiple chemical sensitivities (MCS) R

  • Irreversible Motor Deficits - excitotoxicity and neurodegeneration in the motor cortex (via caspase 3 activation) R

  • Mitochondrial Dysfunction R

  • Reduction in axonal growth (inhibited nerve repair) R

  • Transgenerational poisoning - A pregnant or nursing mother with CFP may transfer to CTX to their fetus or infant R

  • Ulcerative Colitis R

Chronic Ciguatera, Chronic Inflammatory Response Syndrome, and Systemic And Long-term Inflammation

Although symptoms can be acute, persisting symptoms after exposure have been called Chronic Ciguatera (CC) and could be a possible model for Chronic Inflammatory Response Syndrome (CIRS) or Systemic And Long-term Inflammation (SALI). R

3 Major Factors For Chronic Symptoms

When exposure to CTX happens 3, some major pathologies may contribute to it being chronic:

  1. A significant reduction in myelin fibre density, axon demyelination, and axonal degeneration with inflammation (seen in medial insula, medial cingulate cortex, secondary somatosensory cortex, frontal areas, and cerebellum) R

  2. Neuroplastic changes and new epigenetic responses to toxins (as seen in hippocampus) R R

  3. Bioaccumulation in tissue and dysregulation of Activation/Detoxification systems R R

Major Histocompatibility (MHC) Class I Allelic Variation

Also, those with changes in Human Leucocyte Antigen (HLA) and Killer-cell immunoglobulin-like receptor (KIR) may help account for why the severity, diversity, and duration of symptoms cannot be linked solely to the toxin content and/or toxin profile of the seafood ingested. R

For example, in a small case study (4 patients), HLA-B49 haplotype + HLA-DRB1*11 or HLA-DRB1*04 alleles could represent persistent symptoms for CC. R

Coagulation

Ciguatoxin has shown mess with coagualtion. R

For example, ciguatoxin can reduce CD9, a member of the tetraspanin family that when downregulated increases the expression of Matrix Metalloproteinase 9 (MMP9) and thus EGFR. R

Ciguatoxin has also shown to reduce CD36 (thrombospondin receptor). R

Nuclear Enriched Abundant Transcript 1

Ciguatoxin increases expression of Nuclear Enriched Abundant Transcript 1 (NEAT1) in which up-regulation has been seen in response to viral infection and Toll receptor pathways (TLRs), which in turn led to increased binding and sequestration of Interleukin-8 (IL-8) transcriptional repressors. R

NEAT1 is also able to inhibit the expression of Signal Transducer and Activator of Transcription 1 (STAT1). R

Axon Regeneration Pathways

Similarly to CIRS, CTX has shown to reduce genes in Olfactory (OlfR) and Vomeronasal (Vmn) receptors. R

Not only that, but CTX reduces Gonadotropin-Releasing Hormone (GnRH), Vascular Endothelial Growth Factor (VEGF), and Natural Killer (NK)-mediated cytotoxicity. R

Gulf War Syndrome, Chronic Fatigue Syndrome, And Mitochondria

Chronic Fatigue Syndrome (CFS), Gulf War Syndrome (GWS) and CC present in very similar symptoms: fatigue, impaired memory and concentration, tender lymph nodes, muscle/joint pain, headaches, and other neurological impairments. R

In all 3 of these conditions, higher levels of acute phase proteins (such as CRP and SAA) and mitochondrial damage have been seen in the sera of patients. R

CFS patients with HLA-DR/DQ haplotypes have also immune disturbances from biotoxin exposures. R

Ciguatoxin And Brain Fog

 
brain fog.jpg
 

Excitotoxicity and cytokine storms are two main contributors to brain fog.

CTX work on voltage-gated sodium channels (VGSCs) in the brain, changing the activation of neuronal polarity (increases the neuronal excitability by reducing the peak sodium current) and thus causing excitotoxicity and low amounts of glutamate and glutamine. R R

For example, in cortical neurons, CTX exposure (~30min) caused a reduced expression of N-Methyl-D-Aspartic Acid (NMDA) and Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate (AMPA) receptors causing Long-Term Depression (LTD) of glutamate receptors. R

This may be because CTX downregulates the gene Phospholipase A2 (PLA2), which is responsible for NMDA receptor activation as well as neuroprotection against synaptic damage. R R R

CTX can upregulate genes related with stress such as glucocorticoid responsive genes in the brain. R

These changes may last for a while (in the brain) as depolarizing NMDA and AMPA may cause an upregulation in neuroplasatic genes in the hippocampus, such as increase Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF). R R

Also, acute exposure to CTX-1 causes significant reduction in both delta (0–4 Hz) and theta (5–9 Hz) waves in the motor cortex, which is correlated with Alzheimer’s Disease (AD), Schizophrenia, Bipolar Disorder, alcohol/drug abuse, stroke, and epilepsy. R

Ciguatoxin And NAD+ Loss

Speaking of oxidative stress and cytokin storms, CTX can also cause oxidative stress via Nicotinamide Adenine Dinucleotide (NAD+) depletion. R

NAD+ is necessary for protecting against neurodegeneration, and depleting NAD+ within the cell causes increased damage to DNA, mitochondria, and axons. R

This may a be key mechanism as to how ciguatoxins can cause neurodegenerative disease. R

For example, ciguatoxins have shown to cause injury to astrocytes in the anterior cingulate cortex (involved in pain and thermal perception. R

In the liver, CTX causes upregulation of Cytochrome P450 (CYP450) genes in the liver - possibly causing more damage through activation/detoxification dysregulation. R

Testing

There are currently no identified biomarkers that can be used to confirm exposure to CTX in humans, but testing for CIRS biomarkers (ADH, MMP9, TGF-b1, a-MSH, leptin, VIP, C4a, ACTH) may help identify a chronic problem. R R

What To Do About CTX

 
 

Acute CFP is a serious condition and see you healthcare immediately or call poison control if you have been exposed.

  • Avoid contaminated fish or foods (see below)… for example, if I were traveling to the Carribbean, I’d make sure to eat chicken or steak the whole time R

  • Brevenal (see more in red tides post) - blocks CTX-induced catecholamine secretion R

  • Intravenous mannitol - reduces symptoms (especially neurologic) during the acute stage of the illness, and may shorten duration of symptoms after the acute stage. R R R

  • Rosmarinic acid - may protect against ciguatera poisoning, ameliorating the neurotoxic effects of ciguatoxin; rosmarinic acid administered prior to exposure to CTX and restores NAD+ levels in cells, hence reducing oxidative stress R

  • NAV inhibitors (such as lamotrigine and flupirtine) - for pain R

What Makes CTX Worse?

These have all shown to cause recurrence of symptoms: R

  • Alcohol

  • Caffeine

  • Chicken

  • Dehydration

  • Fish (including freshwater species)

  • Nuts

  • Physical Over-Exertion

  • Pork

These recurrences may be from a cumulative exposure, neurological sensitization, cross-sensitization, or metabolic remobilization of CTX from fatty tissue. R

Mechanism Of Action

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243947

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243947

 

Simple:

  • Increases ABCB1 R

  • Increases AEBP1 R

  • Increases ARHGEF1 R

  • Increases ATHL1 R

  • Increases Caspase 3 R

  • Increases CD274 R

  • Increases CELSR3 R

  • Increases CGRP R

  • Increases CYP450 R

  • Increases C17orf66 R

  • Increases C6orf163 R

  • Increases DDX43 R

  • Increases EIF4G3 R

  • Increases FMNL1 R

  • Increases GATA2 R

  • Increases GBP5 R

  • Increases GPR125 R

  • Increases GR R

  • Increases GZMK R

  • Increases HYMAI R

  • Increases LINC00282 R

  • Increases LMF1 R

  • Increases LOC100289090 R

  • Increases LOC345051 R

  • Increases LOC692247 R

  • Increases LRRC37A4P R

  • Increases MAPK R

  • Increases NEAT1 R

  • Increases PDE4DIP R

  • Increases PLGLB1 R

  • Increases SIGLEC14 R

  • Increases SP R

  • Increases TCRBV6 R

  • Increases TCRBV27 R

  • Increases TCRBV28 R

  • Increases TRPA1 R

  • Increases TUBB2A R

  • Increases VIPR2 R

  • Increases ZFP57 R

  • Reduces APCDD1 R

  • Reduces AMPA R

  • Reduces ARHGAP22 R

  • Reduces Calmodulin R

  • Reduces CD36 R

  • Reduces CD9 R

  • Reduces CYB5R2 R

  • Reduces Egr R

  • Reduces FCER1 R

  • Reduces Fos R

  • Reduces Glutamate R

  • Reduces GnRH R

  • Reduces Jun R

  • Reduces HLA-DQB1 (variants 1, 2, and 3) R

  • Reduces IL5RA R

  • Reduces ITGB2 R

  • Reduces LTD R

  • Reduces LYPD2 R

  • Reduces MARCO R

  • Reduces MOR R

  • Reduces NAD+ R

  • Reduces NK activity R

  • Reduces NMDA R

  • Reduces NOD-like receptor R

  • Reduces OlfR R

  • Reduces PADI6 R

  • Reduces PDK4 R

  • Reduces PEX6 R

  • Reduces PKC R

  • Reduces PLC R

  • Reduces PLA2 R

  • Reduces PPP1R17 R

  • Reduces PTK2 R

  • Reduces TOLLIP R

  • Reduces VEGF R

  • Reduces Vmn R

  • Reduces VWF R

Advanced:

  • Similarly to Brevetoxin (PbTx), CTXs (precursor gambiertoxins) are known to preferentially bind to Voltage-Gated Sodium Channels (VGSCs), depolarizing axonal membranes and triggering spontaneous and repetitive action potentials (AP) and causing changes in Na+ and K+, thus disrupting intracellular calcium, neurotransmitter levels, muscular fiber contraction, etc. R R R

  • One animal study showed that CTX administered orally and intraperitoneally was detected four days after exposure in the liver, muscle, and brain. R

  • The lethal potency of CTX1B (LD50) is∼0.25 µg/kg (by intraperitoneal injection into mice). R

  • Human CYP3A4 converts CTX4A and CTX4B to CTX1B, 54-deoxyCTX1B, and 52-epi-54-deoxyCTX1B (in vitro) R

  • CTX-1 activates pain via Calcitonin Gene-Related Peptide (CGRP)/TRPA1 and Substance P (SP). R R

  • Ciguatoxin is slowly metabolized in mammals after ingestion, in rats, the plasma terminal half life was estimated to be 82 and 112 hours after oral and intraperitoneal administration, respectively, with the main route of excretion through the feces. R