Gambierol is a marine polycyclic ether toxin which is produced by the

dinoflagellate The dinoflagellates (Greek δῖνος ''dinos'' "whirling" and Latin ''flagellum'' "whip, scourge") are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered algae. Dinoflagellates are ...

'' Gambierdiscus toxicus''. Gambierol is collected from the sea at the Rangiroa Peninsula in

French Polynesia )Territorial motto: ( en, "Great Tahiti of the Golden Haze") , anthem = , song_type = Regional anthem , song = " Ia Ora 'O Tahiti Nui" , image_map = French Polynesia on the globe (French Polynesia centered).svg , map_alt = Location of Frenc ...

. The toxins are accumulated in fish through the food chain and can therefore cause human

intoxication Intoxication — or poisoning, especially by an alcoholic or narcotic substance — may refer to: * Substance intoxication: ** Alcohol intoxication ** LSD intoxication ** Toxidrome ** Tobacco intoxication ** Cannabis intoxication ** Cocaine in ...

. The symptoms of the toxicity resemble those of ciguatoxins, which are extremely potent neurotoxins that bind to voltage-sensitive sodium channels and alter their function. These ciguatoxins cause ciguatera fish poisoning. Because of the resemblance, there is a possibility that gambierol is also responsible for ciguatera fish poisoning. Because the natural source of gambierol is limited, biological studies are hampered. Therefore, chemical synthesis is required.

Structure and reactivity

Gambierol is a ladder-shaped polyether, composed of eight ether rings, 18 stereocenters, and two challenging pyranyl rings having methyl groups that are in a 1,3-diaxial orientation to one another. Different structural analogues were synthesized to determine which groups and side chains attached to the gambierol are essential for its toxicity. Not only the fused polycyclic ether core is essential, but also the triene side chain at C51 and the C48-C49 double bond were indispensable. In the triene side chain, the double bond between C57 and C58 was essential. The C1 and C8 hydroxy groups were not essential, but they enhance the activity. The conjugate diene in the triene side chain also enhances the toxicity. Gambierol with stereochemistry

Synthesis

The

synthesis Synthesis or synthesize may refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors ** Organic synthesis, the chemical synthesis of organ ...

of gambierol consists of two tetracyclic precursor molecules, one alcohol and one acetic acid, that fuse together. The whole synthesis of gambierol is depicted in the figure below. After obtaining the octacyclic backbone, the tail is added via Stille coupling. The acetic acid (compound 1) and alcohol (compound 2) are converted to compound 3. The reaction of compound 3 with the titanium alkylidene from dibromide 1,1-dibromoethane, provides cyclic enol ether (compound 4). Oxidation of the alcohols gives majorly compound 5, but also compound 6. These are both ketones, but they have other

stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

. Compound 6 can be converted back in compound 5 with reactant c, thereby moving the equilibrium towards compound 5. This ketone can be converted further to produce reactive gambierol. By reductive cyclization of the D ring, the octacyclic core structure (compound 7) was made. Oxidation of compound 7 to the aldehyde was followed by formation of the diiodolefin. Stereoselective reduction, global deprotection and Stille coupling of compound 8 with dienyl stannane (compound 9) provide gambierol. Complete synthesis

Mechanism of action

Gambierol acts as a low-efficacy partial

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

at voltage-gated sodium channels (VGSC’s) and as a high affinity inhibitor of voltage-gated potassium currents. It reduces the current through potassium channels irreversibly by stabilizing some of the closed channels. It acts as an intermembrane anchor where it displaces lipids and prohibits the voltage sensor domain of the channel from moving during physiologically important changes. This causes the channel to remain in the closed state and lowers the current. Gambierol also decreases the amplitude of inward sodium currents and hyperpolarizes the inward sodium current activation. Gambierol has a high affinity for especially K1.1- 1.5 channels and the K3.1 channel. K1.1-1.5 channels are responsible for repolarization of the

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...

. The K1.3 channel however, has additional functions by regulating the Ca²⁺ signaling for T cells. If they are blocked, the T cells at the site of inflammation paralyse and are not reactivated. K3.1 channels are responsible for the high frequency firing of action potentials. If the K channels are closed, the

depolarized In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

membrane cannot repolarize to its resting state, causing a permanent action potential. This leads to paralysis of, for example, the respiratory system and therefore

suffocation Asphyxia or asphyxiation is a condition of deficient supply of oxygen to the body which arises from abnormal breathing. Asphyxia causes generalized hypoxia, which affects primarily the tissues and organs. There are many circumstances that can i ...

of the organism. In neurons, gambierol has been reported to induce Ca oscillations because of blockage of the voltage-gated potassium channels. The Ca oscillations involve

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

release and activation of NMDARs (glutamate receptors). This is however secondary to the blockade of potassium channels. The oscillations reduce the cytoplasmic Ca

threshold Threshold may refer to: Architecture * Threshold (door), the sill of a door Media * ''Threshold'' (1981 film) * ''Threshold'' (TV series), an American science fiction drama series produced during 2005-2006 * "Threshold" (''Stargate SG-1''), ...

for the activation of Ras. Ras stimulates MAPKs to phosphorylate ERK1/2 which induce outgrowth of neurites. This is however dependent on intracellular concentrations and interaction of the NMDAR receptors They both work bidirectionally. An increase in intracellular calcium concentration also activates the nitric oxide synthase to produce

nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

. In combination with a superoxide, nitric oxide forms peroxynitrite and causes oxidative stress in different sorts of tissues. This explains the toxic symptoms derived from intake of gambierol.

Metabolism

Metabolism of gambierol is not known yet, but the expectation is that gambierol acts almost the same as the ciguatoxins. Ciguatoxins are polycyclic polyether compounds. Their molecular weight is between 1.023 and 1.159 Dalton. Gambierol is structurally similar to ciguatoxins and it can be synthesized together with them. Excretion of these ciguatoxins is largely via the feces and in smaller amounts via urine. The compounds are very lipophilic and will therefore diffuse to multiple organs and tissues, for example the liver, fat and the brain. The highest concentration was found in the brain, but muscles contained the highest total amount after a few days. Because gambierol is lipophilic, it can easily persist and accumulate in the fish food chain. The detoxification pathways are still unknown, but it is possible to eliminate the gambierol. This will take several months or years.

Efficacy and side effects

The membrane potential and calcium signaling in T lymphocytes are controlled by ion channels. T cells can be activated if membrane potential and calcium signaling are altered, because they are coupled to

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

pathways. If these signal transduction pathways are disrupted, it can prevent the T cells from responding to antigens. This is called immune suppression. Gambierol is a potent blocker of potassium channels, which for a part determine the membrane potential. Gambierol is therefore a good option for the development of a drug that can be used in immunotherapy. This is for example used in diseases like

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

, diabetes mellitus type 1 and rheumatoid arthritis. Treatment with gambierol is not being used yet, because the compound is toxic and also blocks other channels and thereby disrupts important processes. Intake of gambierol can also cause pain, because Kv1.1 and Kv1.4 channels are blocked and that increases the excitability of central circuits. It also causes illness for several weeks. This is explained by the fact that gambierol is very lipophilic. Lipophilic compounds have high affinity for the lipid bilayer of cell membranes. It is likely that gambierol remains in the cell membrane for days or a few weeks, which explains the long term illness associated with gambierol treatment. There are also other symptoms already explained by the mechanism of action of gambierol, for example difficulties with respiration and hypotension. Gambierol is also an interesting compound in research into treatments of pathologies like Alzheimer’s disease, which are caused by increased expression of β-amyloid and/or tau hyperphosphorylation. Increases in β-amyloid accumulation and/or tau phosphorylation affects neurons the most. The neurons will then be degenerated and therefore this process has effects on the nervous system. However, gambierol can reduce this overexpression of β-amyloid and/or tau hyperphosphorylation in vitro and in vivo. Gambierols function in inducing outgrowth of neurites in a bidirectional manner can potentially be used after neural injury. After for example a trauma or a

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

, gambierol can be used to change the structural plasticity of the brain. The possibility of gambierol to cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

is very important in this case.

Toxicity

Poisoning by gambierol is normally caused after eating contaminated fish. Gambierol exhibits potent toxicity against mice at 50-80 μg/kg by intraperitoneal injection or 150 μg/kg when consumed orally. Symptoms resemble those of ciguatera poisoning. The symptoms concerning the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...

are: * Abdominal pain * Nausea * Vomiting * Diarrhea * Painful defecation The neurological symptoms include: * Paradoxical temperature reversion; cold objects feel hot and vice versa. * Dental pain; teeth feel loose.

First aid

Always contact a doctor. There is no antidote available for gambierol poisoning.

References

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