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Tetrodotoxin

Tetrodotoxin (TTX) is an exogenous neurotoxin found in many marine organisms. The organism most commonly known to contain TTX is the family of Tetraodontidae puffer fish [13]. However, other fish and organisms such as amphibians, arthropods, nematodes, echinoderms, mollusks, dinoflagellate, and bacteria also contain TTX. [6][13] Cases of human poisoning are due to consumption of puffer fish dishes, a delicacy in many Asia countries, especially Japan.

This potent toxin blocks the sodium flow in voltage-gated sodium channels and prevents the generation and propagation of an action potential. This causes physical and motor impairments [6] of numbness, ataxia, aphasia, coma, nausea, stomachache, vomiting and respiratory paralysis that leads to death. [13] Research has focused both on finding an antidote for TTX and on the analgesic properties of TTX as a sodium-channel blocker.

Chemical Structure

Tetrodotoxin is a water-soluble heterocyclic guanidine[4] with a low molecular weight. [6][13] The chemical structure contains a positively charged guanidium group and a pyrimidine ring with hydroxyl groups. [6]

Production and Distribution

TTX-Producing Bacteria

Many types of bacteria produce TTX like the genera Vibrionaceae, Pseudomonas, Aeromonas, Alteromonas, Escherichia coli, Photobacterium phosphoreum, and Plesiomonas shigelloides. [6][15] These bacteria enter the bodies of organisms through a cumulative diet [12][15], however the precise origin of TTX in the food chain is still unknown. [13] Research shows that puffer fish grown in a TTX-free environment had very little amounts of TTX in their tissue.

Distribution of TTX in Animals

In marine animals, the highest concentrations of TTX are in the ovary and liver. In freshwater animals, the highest concentration is found in the skin. [13] In puffer fish, the TTX produced by bacteria is mostly found in the plasma in its unbound form and distributed via the circulatory system. [10][11] The unbound TTX cross vessel walls to be absorbed into the organs. [11] The accumulation of TTX in the liver is thought to be the origin of puffer fish toxification, where the ingested TTX travels through the gastrointestinal system, diffuses into the blood circulation and eventually gathers in the liver in a span of five hours. [10]

When TTX enters the human body, it binds to the external receptor site of the sodium channel. Both the guanidium group and the hydroxyl groups interact with the channel to block sodium flow into the cell. [6]. When TTX binds to segments 5 and 6 in the four domains of a sodium channel[11], the guanidium group forms ion pairs with the negatively charged P-loops of domain 1 and domain 2, while the hydroxyl group forms hydrogen bonds with the glutamic acid in domain 2 and aspartate in domain 4. [6] The rest of the TTX compound is too large to fit through the channel thus effectively blocking sodium entrance into the cell.

Neurotoxic Effects on Sodium Channels Sodium channel blockade leads to a decrease in the amplitude, velocity, and excitability of a nerve potential. Recordings of sensory and motor nerve conduction velocities showed lower velocities in patients poisoned with TTX and slower latent periods than normal. [3][4][8] The overall amplitude of nerve potentials had also decreased due to a decrease in individual nerve potentials and a reduction of sodium permeability across the cell. [4]

The blockade also results in a small hyperpolarization[4] and an increase in threshold potential, causing some neurons completely unable to generate action potentials. [3] The slowness in nerve excitability is especially more prominent in sensory neurons than motor neurons which leads to greater impairments in sensory symptoms, like numbness, rather than motor symptoms such as weakness. [3]

Organisms are resistant to tetrodotoxin due to amino acid substitutions in the pore region of the sodium channel. [6] Many of these organisms have sodium channels that have undergone a mutation with replaces an aromatic amino acid in the P-loop region of domain I with a nonaromatic amino acid. [6][13] Also, TTX-sensitivity can be reduced by neutralizing the negatively charged amino acids in the P-loops and altering the conformational shape of the selectivity filter region of the outer pore. [6] This resistance is not only limited to puffer fish, but to garter snakes, clams, and newts. [13] However, the sodium channel conformational changes leading to TTX resistance can produce a decreased rate of sodium permeability, activation, inactivation or conductance which causes damaged motor capabilities like slower movement. [7][14]

Uses

Female puffer fish release TTX as a pheromone to attract males to fertilize the eggs, as a toxin to protect the eggs and as a defense mechanism against predators through skin excretion. [6][13][14] TTX immunity enables these organisms to prey on TTX-bearing animals that are normally avoided by other predators. [6][7][14]

Recent research has suggested the potential analgesic uses of tetrodotoxin as a sodium channel blocker for reducing pain. [12][13] TTX can act as an effective anesthetic when combined with local anesthetics such as bipuvicaine or vasoconstrictors. Myotoxicity, a harmful side effect of common anesthetics, is significantly reduced when TTX is added. Augmentation of TTX to normal anesthetics produces a longer time period of nerve blockade effects. Also, studies conducted on rats show that a reduction in action potential generation can reduce chronic epileptogenesis. [9] Additional research on rats shows that epilepsy can be prevented when TTX is given with Elvax. [1] TTX as a potential analgesic has been conducted in studies of cancer pain. Sodium channels are found in high density around nociceptive fibers which could be effectively blocked by TTX to elicit a vigorous-pain relieving effect, but further research must be conducted. [2] Although there is no current antidote or neutralizing treatment for TTX poisoning, early detection and treatment of the individual symptoms of TTX poisoning is crucial. Many cases can lead to Grade 3 poisoning, and medical professionals must keep patients under hospital observation even after the potency peak period has passed. [3]