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132-704: Tetrodotoxin ( TTX ) is a potent neurotoxin . Its name derives from Tetraodontiformes , an order that includes pufferfish , porcupinefish , ocean sunfish , and triggerfish ; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals (e.g., in blue-ringed octopi , rough-skinned newts , and moon snails ). It is also produced by certain infectious or symbiotic bacteria like Pseudoalteromonas , Pseudomonas , and Vibrio as well as other species found in symbiotic relationships with animals and plants. Although it produces thousands of intoxications annually and several deaths, it has shown efficacy for

264-483: A North American newt known for the strong toxin exuded from its skin. A stocky newt with rounded snout, it ranges from light brown to olive or brownish-black on top, with the underside, including the head, legs, and tail, a contrasting orange to yellow. The skin is granular, but males are smooth-skinned during breeding season. They measure 6 to 9 cm (2.4 to 3.5 in) in snout-to-vent length, and 11 to 18 cm (4.3 to 7.1 in) overall. They are similar to

396-409: A coma . If the patient survives 24 hours, recovery without any aftereffects will usually occur over a few days. Therapy is supportive and based on symptoms, with aggressive early airway management. If consumed, treatment can consist of emptying the stomach, feeding the victim activated charcoal to bind the toxin, and taking standard life-support measures to keep the victim alive until the effect of

528-423: A exposure are loss of coordination, twitching , convulsions and rapid death by respiratory paralysis . The nerve tissues which communicate with muscles contain a receptor called the nicotinic acetylcholine receptor . Stimulation of these receptors causes a muscular contraction . The anatoxin- a molecule is shaped so it fits this receptor, and in this way it mimics the natural neurotransmitter normally used by

660-444: A metabolite of arsenic, arsenite is formed after ingestion of arsenic and has shown significant toxicity to neurons within about 24 hours of exposure. The mechanism of this cytotoxicity functions through arsenite-induced increases in intracellular calcium ion levels within neurons, which may subsequently reduce mitochondrial transmembrane potential which activates caspases , triggering cell death. Another known function of arsenite

792-869: A Rover . But this theory has been questioned by the scientific community since the 1990s based on analytical chemistry -based tests of multiple preparations and review of earlier reports (see above). Neurotoxin Neurotoxins inhibit neuron control over ion concentrations across the cell membrane, or communication between neurons across a synapse . Local pathology of neurotoxin exposure often includes neuron excitotoxicity or apoptosis but can also include glial cell damage. Macroscopic manifestations of neurotoxin exposure can include widespread central nervous system damage such as intellectual disability , persistent memory impairments, epilepsy , and dementia . Additionally, neurotoxin-mediated peripheral nervous system damage such as neuropathy or myopathy

924-575: A biochemical probe has elucidated two distinct types of voltage-gated sodium channels (VGSCs) present in mammals: tetrodotoxin-sensitive voltage-gated sodium channels (TTX-s Na channels) and tetrodotoxin-resistant voltage-gated sodium channels (TTX-r Na channels). Tetrodotoxin inhibits TTX-s Na channels at concentrations of around 1–10 nM, whereas micromolar concentrations of tetrodotoxin are required to inhibit TTX-r Na channels. Nerve cells containing TTX-r Na channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na channels dominate

1056-433: A category of poisons produced by the marine cone snail, and are capable of inhibiting the activity of a number of ion channels such as calcium, sodium, or potassium channels. In many cases, the toxins released by the different types of cone snails include a range of different types of conotoxins, which may be specific for different ion channels, thus creating a venom capable of widespread nerve function interruption. One of

1188-461: A consequence of increased concentrations, ammonia activity in-vivo has been shown to induce swelling of astrocytes in the brain through increased production of cGMP (Cyclic Guanosine Monophosphate) within the cells which leads to Protein Kinase G-mediated (PKG) cytoskeletal modifications. The resultant effect of this toxicity can be reduced brain energy metabolism and function. Importantly,

1320-580: A diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a case of fatal overdosage. Most analytical techniques involve mass spectrometric detection following gas or liquid chromatographic separation. Tetrodotoxin has been investigated as a possible treatment for cancer-associated pain. Early clinical trials demonstrate significant pain relief in some patients. It has also been studied in relation to migraine headaches. Mutations in one particular TTX-sensitive Na channel are associated with some migraine headaches, although it

1452-501: A factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming animal species known to contain tetrodotoxin, principally pufferfish; other tetrodotoxic species are not usually consumed by humans. Poisoning from tetrodotoxin is of particular public health concern in Japan, where fugu is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed chefs carefully remove

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1584-401: A form of chemical based avoidance behavior to avoid being eaten by predators, mainly the common garter snake. The snakes, after swallowing, digesting, and metabolizing a rough-skinned newt, release a chemical signature. This stimulus can be detected by a nearby newt and trigger an avoidant response, which allows them to minimize predation risks. In this way, newts are able to differentiate whether

1716-450: A heightened resistance. The toxin in newts consists of a tradeoff. Each time they release the toxin, they inject themselves with a few milligrams. The TTX becomes concentrated in certain parts of the tissue after passing through cell membranes. As a result of tissue exposure to the toxin, newts have evolved a protection mechanism via a single amino acid substitution to the voltage-gated sodium channel normally affected by TTX. Puffer fishes show

1848-414: A more accurate distinction between true neurotoxins and cytotoxins in an in-vitro testing environment. Due to the significant inaccuracies associated with this process, however, it has been slow in gaining widespread support. Additionally, biochemical mechanisms have become more widely used in neurotoxin testing, such that compounds can be screened for sufficiency to induce cell mechanism interference, like

1980-463: A number of potential chemical insults. This barrier creates a tight hydrophobic layer around the capillaries in the brain, inhibiting the transport of large or hydrophilic compounds. In addition to the BBB, the choroid plexus provides a layer of protection against toxin absorption in the brain. The choroid plexuses are vascularized layers of tissue found in the third, fourth, and lateral ventricles of

2112-669: A plot device for characters to fake death, as in the films Hello Again (1987), The Serpent and the Rainbow (1988), The A-Team (2010) and Captain America: The Winter Soldier (2014), War (2019), and in episodes of " Jane the Virgin ", Miami Vice (1985), Nikita , MacGyver Season 7, Episode 6, where the antidote is Datura stramonium leaf, CSI: NY (Season 4, episode 9 "Boo") and Chuck . In Law Abiding Citizen (2009) and Alex Cross (2012), its paralysis

2244-400: A postsynaptic neuron. The effect of this increased signaling threshold is a reduced excitability of postsynaptic neurons , and subsequent loss of motor and sensory function which can result in paralysis and death. Though assisted ventilation may increase the chance of survival after TTX exposure, there is currently no antitoxin. The use of the acetylcholinesterase inhibitor Neostigmine or

2376-603: A predator or prey very rapidly, toxins have evolved to become highly specific to their target channels such that the toxin does not readily bind other targets (see Ion Channel toxins ). As such, neurotoxins provide an effective means by which certain elements of the nervous system may be accurately and efficiently targeted. An early example of neurotoxin based targeting used radiolabeled tetrodotoxin to assay sodium channels and obtain precise measurements about their concentration along nerve membranes . Likewise through isolation of certain channel activities, neurotoxins have provided

2508-658: A restaurant, while the others all involved fishermen eating their catch. From 2006 through 2009 in Japan there were 119 incidents involving 183 people but only seven people died. Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare. In Haiti, tetrodotoxin was thought to have been used in voodoo preparations, in so-called zombie poisons. Subsequent careful analysis has however repeatedly called early studies into question on technical grounds, and failed to identify

2640-400: A result of direct lethality of glutamate on neurons and a result of induced calcium flux into neurons leading to swelling and necrosis. Support has been shown for these mechanisms playing significant roles in diseases and complications such as Huntington's disease , epilepsy , and stroke . Taricha granulosa The rough-skinned newt or roughskin newt ( Taricha granulosa ) is

2772-453: A result of early lead exposure. In addition to inducing apoptosis, lead inhibits interneuron signaling through the disruption of calcium-mediated neurotransmitter release. As a neurotoxin, ethanol has been shown to induce nervous system damage and affect the body in a variety of ways. Among the known effects of ethanol exposure are both transient and lasting consequences. Some of the lasting effects include long-term reduced neurogenesis in

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2904-438: A result of increased generation of reactive oxidative species (ROS). This is a plausible mechanism, as there is a reduced presence in the fetal brain of antioxidant enzymes such as catalase and peroxidase . In support of this mechanism, administration of high levels of dietary vitamin E results in reduced or eliminated ethanol-induced neurotoxic effects in fetuses. n- Hexane is a neurotoxin which has been responsible for

3036-445: A role in TTX biosynthesis" – although the correlation has been extended to most but not all animals in which the toxin has been identified. To the contrary, there has been a failure in a single case, that of newts ( Taricha granulosa ), to detect TTX-producing bacteria in the tissues with highest toxin levels ( skin , ovaries , muscle ), using PCR methods, although technical concerns about

3168-409: A similar amino acid sequence that allows them to survive from their own toxin exposure. Predation on newts by T. sirtalis also shows evidence that tetrodotoxin may serve as protection of eggs by the mother. While TTX is mainly located in the glands of the skin, the rough-skinned newt, as well as some other amphibians also possesses TTX in the ovaries and eggs. The higher the skin toxin levels were in

3300-408: A snake is resistant or sensitive to the toxin in order to avoid being preyed upon. However, newts do not avoid the corpses of a recently digested newt that has been left to decompose. This behavior is unlike salamanders that have been documented in avoiding other injured salamanders. Parasites include the trematode Halipegus occidualis , the adult form of which may infest the newt's esophagus and

3432-512: A strong case is made for ingestion of TTX and/or TTX-producing bacteria, with accumulation and possible subsequent colonization and production. Nevertheless, without clear biosynthetic pathways (not yet found in animals, but shown for bacteria), it remains uncertain whether it is simply via bacteria that each animal accumulates TTX; the question remains as to whether the quantities can be sufficiently explained by ingestion, ingestion plus colonization, or some other mechanism. Tetrodotoxin binds to what

3564-597: A tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish, and at least one report of a fatal episode in Oregon when an individual swallowed a rough-skinned newt Taricha granulosa on a dare. In 2009, a major scare in the Auckland Region of New Zealand was sparked after several dogs died eating Pleurobranchaea maculata (grey side-gilled seaslug) on beaches. Children and pet owners were asked to avoid beaches, and recreational fishing

3696-539: A tonic effect when used at the correct dose. The principal use was "to arrest convulsive diseases". In the Pen-T’so Kang Mu (Index Herbacea or The Great Herbal by Li Shih-Chen, 1596) some types of the fish Ho-Tun (the current Chinese name for tetraodon ) were also recognized as both toxic yet, at the right dose, useful as part of a tonic. Increased toxicity in Ho-Tun was noted in fish caught at sea (rather than river) after

3828-610: Is a neurotoxin commonly found concentrated in areas exposed to agricultural runoff , mining , and smelting sites (Martinez-Finley 2011). One of the effects of arsenic ingestion during the development of the nervous system is the inhibition of neurite growth which can occur both in PNS and the CNS. This neurite growth inhibition can often lead to defects in neural migration , and significant morphological changes of neurons during development , ) often leading to neural tube defects in neonates . As

3960-428: Is a new nonpeptide amino acid toxin that stimulate the glutamate receptors in neurons. Caramboxin is an agonist of both NMDA and AMPA glutamatergic ionotropic receptors with potent excitatory, convulsant, and neurodegenerative properties. The term " curare " is ambiguous because it has been used to describe a number of poisons which at the time of naming were understood differently from present day understandings. In

4092-411: Is a particularly useful molecule for investigating acetylcholine receptors in the nervous system. The deadliness of the toxin means that it has a high military potential as a toxin weapon. Bungarotoxin is a compound with known interaction with nicotinic acetylcholine receptors (nAChRs), which constitute a family of ion channels whose activity is triggered by neurotransmitter binding. Bungarotoxin

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4224-471: Is a poison produced by organisms belonging to the Tetraodontiformes order , which includes the puffer fish , ocean sunfish , and porcupine fish . Within the puffer fish, TTX is found in the liver , gonads , intestines , and skin . TTX can be fatal if consumed, and has become a common form of poisoning in many countries. Common symptoms of TTX consumption include paraesthesia (often restricted to

4356-431: Is a potent neurotoxin whose toxicity has been recognized for at least thousands of years. Though neurotoxic effects for lead are found in both adults and young children , the developing brain is particularly susceptible to lead-induced harm, effects which can include apoptosis and excitotoxicity. An underlying mechanism by which lead is able to cause harm is its ability to be transported by calcium ATPase pumps across

4488-453: Is based on its importance in glutamate excitotoxicity, as NO is generated in a calcium-dependent manner in response to glutamate mediated NMDA activation, which occurs at an elevated rate in glutamate excitotoxicity. Though NO facilitates increased blood flow to potentially ischemic regions of the brain, it is also capable of increasing oxidative stress , inducing DNA damage and apoptosis. Thus an increased presence of NO in an ischemic area of

4620-471: Is common. Support has been shown for a number of treatments aimed at attenuating neurotoxin-mediated injury, such as antioxidant and antitoxin administration. Exposure to neurotoxins in society is not new, as civilizations have been exposed to neurologically destructive compounds for thousands of years. One notable example is the possible significant lead exposure during the Roman Empire resulting from

4752-521: Is in development by USAMRIID that was effective, in the one study, for reducing toxin lethality in tests on mice. Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific Ocean regions, primarily because equally toxic pufferfishes from other regions are much less commonly eaten. Several reported cases of poisonings, including fatalities, nonetheless involved pufferfish from

4884-507: Is increasing respiratory distress , speech is affected, and the victim usually exhibits shortness of breath , excess pupil dilation , and abnormally low blood pressure . Paralysis increases, and convulsions , mental impairment, and irregular heartbeats may occur. The victim, although completely paralysed, may be conscious and in some cases completely understandable until shortly before death, which generally occurs within 4 to 6 hours (range ~20 minutes to ~8 hours). However, some victims enter

5016-483: Is its destructive nature towards the cytoskeleton through inhibition of neurofilament transport. This is particularly destructive as neurofilaments are used in basic cell structure and support. Lithium administration has shown promise, however, in restoring some of the lost neurofilament motility. Additionally, similar to other neurotoxin treatments, the administration of certain antioxidants has shown some promise in reducing neurotoxicity of ingested arsenic. Lead

5148-410: Is known as site 1 of the fast voltage-gated sodium channel . Site 1 is located at the extracellular pore opening of the ion channel. Any molecule bound to this site will block sodium ions from going into the nerve cell through this channel (which is ultimately necessary for nerve conduction). Saxitoxin , neosaxitoxin , and several of the conotoxins also bind the same site. The use of this toxin as

5280-459: Is much larger than a sodium ion, it acts like a cork in a bottle and prevents the flow of sodium. The reverse binding to sodium channels in nerve cells blocks electrical signals necessary for conducting nerve impulses. This inhibition of firing action potentials has the effect of inducing paralysis and death by asphyxiation. Throughout much of the newt's range, the common garter snake ( Thamnophis sirtalis ) has been observed to exhibit resistance to

5412-560: Is needed to kill any other conceivable predator. Some newts secrete enough toxins to kill several adult humans. It appears that in some areas, the common garter snake has surpassed the newt in the evolutionary arms race by developing such a strong resistance to the toxin that the newt is unable to compete with its production of the toxin. There has been phylogenetic evidence that indicates elevated resistance to TTX has originated independently and only in certain species of garter snakes. The resistance has evolved in at least two unrelated species in

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5544-523: Is no longer valid, as specimens that look similar to T.g.m. have been found in areas of Alaska as well. Many newts produce toxins from skin glands as a defense against predation , but the toxins of the genus Taricha are particularly potent. An acrid smell radiates from the newt, which acts as a warning for animals to stay away. Toxicity is generally experienced only if the newt is ingested, although some individuals have been reported to experience skin irritation after dermal contact, particularly if

5676-400: Is often seen through two routes of administration, either through consumption or through endogenous ailments such as liver failure . One notable case in which ammonia toxicity is common is in response to cirrhosis of the liver which results in hepatic encephalopathy , and can result in cerebral edema (Haussinger 2006). This cerebral edema can be the result of nervous cell remodeling. As

5808-402: Is only partially understood. It is long known that the molecule is related to saxitoxin , and as of 2011 it is believed that there are separate routes for aquatic (bacterial) and terrestrial (newt) TTX. In 2020, new intermediates found in newts suggest that the synthesis starts with geranyl guanidine in the amphibian; these intermediates were not found in aquatic TTX-containing animals, supporting

5940-532: Is particularly specific for α7-nAChR . This α7-nAChR functions to allow calcium ion influx into cells, and thus when blocked by ingested bungarotoxin will produce damaging effects, as ACh signaling will be inhibited. Likewise, the use of α-bungarotoxin can be very useful in neuroscience if it is desirable to block calcium flux in order to isolate effects of other channels. Additionally, different forms of bungarotoxin may be useful for studying inhibited nAChRs and their resultant calcium ion flow in different systems of

6072-646: Is presented as a method of assisting torture. The toxin was also referenced in "synthetic form" in the S1E2 of the series " FBI ". The toxin is used as a weapon in both the second season of Archer , in Covert Affairs and in the Inside No. 9 episode " The Riddle of the Sphinx ". In Columbo, Episode 2 of Season 7, fugu is used to kill the antagonists victim. Columbo (season 7) In The Apothecary Diaries light novel, as well as

6204-494: Is produced in a number of different forms, though one of the commonly used forms is the long chain alpha form, α-bungarotoxin , which is isolated from the banded krait snake . Though extremely toxic if ingested, α-bungarotoxin has shown extensive usefulness in neuroscience as it is particularly adept at isolating nAChRs due to its high affinity to the receptors. As there are multiple forms of bungarotoxin, there are different forms of nAChRs to which they will bind, and α-bungarotoxin

6336-822: Is the ability for ethanol to inhibit NMDA receptors in the hippocampus, resulting in reduced long-term potentiation (LTP) and memory acquisition. NMDA has been shown to play an important role in LTP and consequently memory formation. With chronic ethanol intake, however, the susceptibility of these NMDA receptors to induce LTP increases in the mesolimbic dopamine neurons in an inositol 1,4,5-triphosphate (IP3) dependent manner. This reorganization may lead to neuronal cytotoxicity both through hyperactivation of postsynaptic neurons and through induced addiction to continuous ethanol consumption. It has, additionally, been shown that ethanol directly reduces intracellular calcium ion accumulation through inhibited NMDA receptor activity, and thus reduces

6468-405: Is this capability to inhibit potassium flux in neurons that has made TEA one of the most important tools in neuroscience. It has been hypothesized that the ability for TEA to inhibit potassium channels is derived from its similar space-filling structure to potassium ions. What makes TEA very useful for neuroscientists is its specific ability to eliminate potassium channel activity, thereby allowing

6600-547: Is unclear as to whether this has any therapeutic relevance for most people with migraine. Tetrodotoxin has been used clinically to relieve negative affects associated with heroin withdrawal . In the U.S., tetrodotoxin appears on the select agents list of the Department of Health and Human Services , and scientists must register with HHS to use tetrodotoxin in their research. However, investigators possessing less than 500 mg are exempt from regulation. Tetrodotoxin serves as

6732-536: Is usually associated is muscle paralysis and resultant death. Curare notably functions to inhibit nicotinic acetylcholine receptors at the neuromuscular junction . Normally, these receptor channels allow sodium ions into muscle cells to initiate an action potential that leads to muscle contraction. By blocking the receptors, the neurotoxin is capable of significantly reducing neuromuscular junction signaling, an effect which has resulted in its use by anesthesiologists to produce muscular relaxation. Ammonia toxicity

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6864-543: The Cascade Mountains , though occasionally are found (and considered exotic, and possibly artificially introduced) as far as Montana. One isolated population lives in several ponds just north of Moscow, Idaho , and was most likely introduced. A number of subspecies have been defined based on local variants, but only two subspecies have wider recognition: It is now believed that the Taricha granulosa mazamae subspecies

6996-571: The TRPV1 receptor expressed on cholinergic neurons and inhibit the toxic effects of BTX. Tetanus neurotoxin (TeNT) is a compound that functionally reduces inhibitory transmissions in the nervous system resulting in muscular tetany. TeNT is similar to BTX, and is in fact highly similar in structure and origin; both belonging to the same category of clostridial neurotoxins . Like BTX, TeNT inhibits inter-neuron communication by means of vesicular neurotransmitter (NT) release. One notable difference between

7128-539: The hippocampus , widespread brain atrophy, and induced inflammation in the brain. Of note, chronic ethanol ingestion has additionally been shown to induce reorganization of cellular membrane constituents, leading to a lipid bilayer marked by increased membrane concentrations of cholesterol and saturated fat . This is important as neurotransmitter transport can be impaired through vesicular transport inhibition, resulting in diminished neural network function. One significant example of reduced inter-neuron communication

7260-436: The mouth and limbs ), muscle weakness, nausea , and vomiting and often manifest within 30 minutes of ingestion . The primary mechanism by which TTX is toxic is through the inhibition of sodium channel function, which reduces the functional capacity of neuron communication. This inhibition largely affects a susceptible subset of sodium channels known as TTX-sensitive (TTX-s), which also happens to be largely responsible for

7392-662: The viscera to reduce the danger of poisoning. There is potential for misidentification and mislabelling, particularly of prepared, frozen fish products. The mouse bioassay developed for paralytic shellfish poisoning (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An HPLC method with post-column reaction with alkali and fluorescence has been developed to determine tetrodotoxin and its associated toxins. The alkali degradation products can be confirmed as their trimethylsilyl derivatives by gas chromatography/mass spectrometry. Tetrodotoxin may be quantified in serum, whole blood or urine to confirm

7524-652: The 1938 non-fiction book Tell My Horse by Zora Neale Hurston in which there were multiple accounts of purported tetrodotoxin poisoning in Haiti by a voodoo sorcerer called the bokor . These stories were later popularized by Harvard -trained ethnobotanist Wade Davis in his 1985 book and Wes Craven 's 1988 film, both titled The Serpent and the Rainbow . James Ellroy includes "blowfish toxin" as an ingredient in Haitian Vodou preparations to produce zombieism and poisoning deaths in his dark, disturbing, violent novel Blood's

7656-692: The Atlantic Ocean, Gulf of Mexico , and Gulf of California . There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, Sphoeroides maculatus , but three studies found extracts from fish of this species highly toxic in mice. Several recent intoxications from these fishes in Florida were due to saxitoxin , which causes paralytic shellfish poisoning with very similar symptoms and signs. The trumpet shell Charonia sauliae has been implicated in food poisonings, and evidence suggests it contains

7788-439: The BBB, allowing for direct contact with the fragile cells within the central nervous system. Neurotoxicity results from lead's ability to act in a similar manner to calcium ions, as concentrated lead will lead to cellular uptake of calcium which disrupts cellular homeostasis and induces apoptosis. It is this intracellular calcium increase that activates protein kinase C (PKC), which manifests as learning deficits in children as

7920-637: The BBB. To even further complicate the process of determining neurotoxins when testing in-vitro, neurotoxicity and cytotoxicity may be difficult to distinguish as exposing neurons directly to compounds may not be possible in-vivo, as it is in-vitro. Additionally, the response of cells to chemicals may not accurately convey a distinction between neurotoxins and cytotoxins, as symptoms like oxidative stress or skeletal modifications may occur in response to either. In an effort to address this complication, neurite outgrowths (either axonal or dendritic) in response to applied compounds have recently been proposed as

8052-448: The CNS can produce significantly toxic effects. Glutamate , like nitric oxide, is an endogenously produced compound used by neurons to perform normally, being present in small concentrations throughout the gray matter of the CNS. One of the most notable uses of endogenous glutamate is its functionality as an excitatory neurotransmitter. When concentrated, however, glutamate becomes toxic to surrounding neurons. This toxicity can be both

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8184-559: The California newt ( Taricha torosa ) but differ in having smaller eyes, yellow irises, V-shaped tooth patterns, and uniformly dark eyelids. Males can be distinguished from females during breeding season by large swollen vent lobes and cornified toe pads. Habitats of rough-skinned newts are found throughout the Pacific Northwest . Their range extends south to Santa Cruz, California , and north to Alaska . They are uncommon east of

8316-477: The ability to improve the original Hodgkin-Huxley model of the neuron in which it was theorized that single generic sodium and potassium channels could account for most nervous tissue function. From this basic understanding, the use of common compounds such as tetrodotoxin, tetraethylammonium , and bungarotoxins have led to a much deeper understanding of the distinct ways in which individual neurons may behave. As neurotoxins are compounds which adversely affect

8448-410: The amount needed to reach a lethal dose by injection is 8 μg per kg in mice. The toxin can enter the body of a victim by ingestion , injection, or inhalation , or through abraded skin. Poisoning occurring as a consequence of consumption of fish from the order Tetraodontiformes is extremely serious. The organs (e.g., liver) of the pufferfish can contain levels of tetrodotoxin sufficient to produce

8580-404: The amount of newt then apply a selective pressure favoring snakes with mutations conferring even greater resistance. This cycle of a predator and prey evolving to one another is sometimes termed an evolutionary arms race because the two species compete in developing adaptations and counter adaptations against each other. This has resulted in the newts producing levels of toxin far in excess of what

8712-421: The approach have been raised. Critically for the general argument, Takifugu rubripes puffers captured and raised in laboratory on controlled, TTX-free diets "lose toxicity over time", while cultured, TTX-free Takifugu niphobles puffers fed on TTX-containing diets saw TTX in the livers of the fishes increase to toxic levels. Hence, as bacterial species that produce TTX are broadly present in aquatic sediments,

8844-449: The blood, such as those experiencing renal failure . Patients experiencing aluminium toxicity can exhibit symptoms such as impaired learning and reduced motor coordination . Additionally, systemic aluminium levels are known to increase with age, and have been shown to correlate with Alzheimer's disease , implicating it as a neurotoxic causative compound of the disease. Despite its known toxicity in its ionic form, studies are divided on

8976-457: The body and brain. As a result, TTX causes loss of sensation, and paralysis of voluntary muscles including the diaphragm and intercostal muscles, stopping breathing. The therapeutic uses of puffer fish ( tetraodon ) eggs were mentioned in the first Chinese pharmacopoeia Pen-T’so Ching (The Book of Herbs, allegedly 2838–2698 BC by Shennong ; but a later date is more likely ), where they were classified as having "medium" toxicity, but could have

9108-432: The body in useful and healthy ways, such as nitric oxide which is used in cell communication. It is often only when these endogenous compounds become highly concentrated that they lead to dangerous effects. Though nitric oxide (NO) is commonly used by the nervous system in inter-neuron communication and signaling, it can be active in mechanisms leading to ischemia in the cerebrum (Iadecola 1998). The neurotoxicity of NO

9240-444: The body. For example, α-bungarotoxin is specific for nAChRs found in the musculature and κ-bungarotoxin is specific for nAChRs found in neurons. Caramboxin (CBX) is a toxin found in star fruit ( Averrhoa carambola) . Individuals with some types of kidney disease are susceptible to adverse neurological effects including intoxication, seizures and even death after eating star fruit or drinking juice made of this fruit. Caramboxin

9372-485: The brain , which through the function of their ependymal cells, are responsible for the synthesis of cerebrospinal fluid (CSF). Importantly, through selective passage of ions and nutrients and trapping heavy metals such as lead, the choroid plexuses maintain a strictly regulated environment which contains the brain and spinal cord. By being hydrophobic and small, or inhibiting astrocyte function, some compounds including certain neurotoxins are able to penetrate into

9504-427: The brain and induce significant damage. In modern times, scientists and physicians have been presented with the challenge of identifying and treating neurotoxins, which has resulted in a growing interest in both neurotoxicology research and clinical studies. Though clinical neurotoxicology is largely a burgeoning field, extensive inroads have been made in the identification of many environmental neurotoxins leading to

9636-419: The brain and inhibit some of the crucial functions of the blood brain barrier (BBB). A loss of function in the BBB can produce significant damage to the neurons in the CNS, as the barrier protecting the brain from other toxins found in the blood will no longer be capable of such action. Though the metal is known to be neurotoxic, effects are usually restricted to patients incapable of removing excess ions from

9768-412: The brain requires nutrient entry and waste removal, it is perfused by blood flow. Blood can carry a number of ingested toxins, however, which would induce significant neuron death if they reach nervous tissue. Thus, protective cells termed astrocytes surround the capillaries in the brain and absorb nutrients from the blood and subsequently transport them to the neurons, effectively isolating the brain from

9900-549: The brain such as vitamin E . As the fetal brain is relatively fragile and susceptible to induced stresses, severe deleterious effects of alcohol exposure can be seen in important areas such as the hippocampus and cerebellum . The severity of these effects is directly dependent upon the amount and frequency of ethanol consumption by the mother, and the stage in development of the fetus. It is known that ethanol exposure results in reduced antioxidant levels, mitochondrial dysfunction (Chu 2007), and subsequent neuronal death, seemingly as

10032-693: The capacity for the occurrence of LTP. In addition to the neurotoxic effects of ethanol in mature organisms, chronic ingestion is capable of inducing severe developmental defects. Evidence was first shown in 1973 of a connection between chronic ethanol intake by mothers and defects in their offspring. This work was responsible for creating the classification of fetal alcohol syndrome , a disease characterized by common morphogenesis aberrations such as defects in craniofacial formation, limb development, and cardiovascular formation. The magnitude of ethanol neurotoxicity in fetuses leading to fetal alcohol syndrome has been shown to be dependent on antioxidant levels in

10164-507: The case of botulinum toxin , or even nervous tissue death. The time required for the onset of symptoms upon neurotoxin exposure can vary between different toxins, being on the order of hours for botulinum toxin and years for lead. Tetanus toxin Mercury Curare Caramboxin , 25I-NBOMe , JWH-018 , 5-MEO-DiPT Arsenic N-Hexane , Methanol Glutamate , Dopamine Tetrodotoxin (TTX)

10296-514: The classification of 750 to 1000 known potentially neurotoxic compounds. Due to the critical importance of finding neurotoxins in common environments, specific protocols have been developed by the United States Environmental Protection Agency (EPA) for testing and determining neurotoxic effects of compounds (USEPA 1998). Additionally, in vitro systems have increased in use as they provide significant improvements over

10428-438: The conductance of chloride channels . Ingestion of lethal volumes of Cltx results in paralysis through this ion channel disruption. Similar to botulinum toxin, Cltx has been shown to possess significant therapeutic value. Evidence has shown that Cltx can inhibit the ability for gliomas to infiltrate healthy nervous tissue in the brain, significantly reducing the potential invasive harm caused by tumors. Conotoxins represent

10560-522: The deaths of cows that drank from a lake containing an algal bloom in Saskatchewan, Canada. It is a cyanotoxin produced by at least four different genera of cyanobacteria , and has been reported in North America, Europe, Africa, Asia, and New Zealand. Toxic effects from anatoxin- a progress very rapidly because it acts directly on the nerve cells ( neurons ). The progressive symptoms of anatoxin-

10692-402: The described paralysis of the diaphragm and corresponding death due to respiratory failure . Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not be dangerously toxic. The mechanism of toxicity is through the blockage of fast voltage-gated sodium channels, which are required for the normal transmission of signals between

10824-498: The development of extensive plumbing networks and the habit of boiling vinegared wine in lead pans to sweeten it, the process generating lead acetate, known as "sugar of lead". In part, neurotoxins have been part of human history because of the fragile and susceptible nature of the nervous system, making it highly prone to disruption. The nervous tissue found in the brain , spinal cord , and periphery comprises an extraordinarily complex biological system that largely defines many of

10956-401: The disruption or destruction of necessary components within the nervous system . Neurotoxins, however, by their very design can be very useful in the field of neuroscience . As the nervous system in most organisms is both highly complex and necessary for survival, it has naturally become a target for attack by both predators and prey. As venomous organisms often use their neurotoxins to subdue

11088-489: The effects of TTX. Mutations in the VGSC genes, especially the genes for Na v 1.4 (skeletal muscle VGSC, "TTX-s"), are found in many such animals. These mutations have independently arisen several times, even multiple times in different populations of the same species as seen in the garter snake. They consist of different amino acid substitutions in similar positions, a weak example of convergent evolution caused by how TTX binds to

11220-475: The eyes are touched after handling the animal without washing hands. In 1979, a 29-year-old man from Oregon died after ingesting a rough-skinned newt. The newt produces a neurotoxin called tetrodotoxin (TTX), which in this species was formerly called "tarichatoxin". It is the same toxin found in pufferfish and a number of other marine animals. This toxin targets voltage-gated sodium channels via binding to distinct but allosterically coupled sites. Because TTX

11352-409: The female, the higher the toxin level found in the egg. This is evidence that high toxin levels of the skin may, in fact, be under indirect selection. Since egg toxin levels would ultimately increase the survivability from predators, such as the garter snake, of the offspring, egg toxin levels may be under direct selection by mates, which is detectable via skin toxin levels. The rough skinned newt uses

11484-600: The fish were, to the extent that it would be used for suicide and that the Emperor specifically decreed that soldiers were not permitted to eat it. There is also evidence from other sources that knowledge of such toxicity was widespread throughout southeast Asia and India. The first recorded cases of TTX poisoning affecting Westerners are from the logs of Captain James Cook from 7 September 1774. On that date Cook recorded his crew eating some local tropic fish (pufferfish), then feeding

11616-470: The following animals, specific bacterial species have been implicated: The association of bacterial species with the production of the toxin is unequivocal – Lago and coworkers state, "[e]ndocellular symbiotic bacteria have been proposed as a possible source of eukaryotic TTX by means of an exogenous pathway", and Chau and coworkers note that the "widespread occurrence of TTX in phylogenetically distinct organisms... strongly suggests that symbiotic bacteria play

11748-455: The function of motor nerves and thus the contraction of the musculature in a manner similar to that of curare. Additionally, through chronic TEA administration, muscular atrophy would be induced. It was later determined that TEA functions in-vivo primarily through its ability to inhibit both the potassium channels responsible for the delayed rectifier seen in an action potential and some population of calcium-dependent potassium channels. It

11880-401: The genus Thamnophis and at least twice within T. sirtalis . The toxin, when injected into animals, may not kill resistant animals; however, they are normally slowed down by its toxic effects. In snakes, individuals who showed some resistance tended to move slower after TTX injection, while those with less resistance become paralyzed. Newts are not immune to their own toxin; they only have

12012-515: The identity of maculotoxin and TTX was reported in Science in 1978, and the synonymity of these two toxins is supported in modern reports (e.g., at Pubchem and in modern toxicology textbooks) though historic monographs questioning this continue in reprint. The toxin is variously used by animals as a defensive biotoxin to ward off predation , or as both a defensive and predatory venom (e.g., in octopuses, chaetognaths , and ribbon worms ). Even though

12144-449: The inhibition of acetylcholinesterase capacity of organophosphates (includes parathion and sarin gas). Though methods of determining neurotoxicity still require significant development, the identification of deleterious compounds and toxin exposure symptoms has undergone significant improvement. Though diverse in chemical properties and functions, neurotoxins share the common property that they act by some mechanism leading to either

12276-416: The lips and tongue is followed by developing it in the extremities, hypersalivation , sweating , headache, weakness, lethargy, incoordination , tremor , paralysis, bluish skin , loss of voice , difficulty swallowing , and seizures . The gastrointestinal symptoms are often severe and include nausea , vomiting , diarrhoea , and abdominal pain ; death is usually secondary to respiratory failure . There

12408-463: The membranes of neurons but not those of muscle cells. Botulinum toxin (BTX) is a group of neurotoxins consisting of eight distinct compounds, referred to as BTX-A,B,C,D,E,F,G,H, which are produced by the bacterium Clostridium botulinum and lead to muscular paralysis . A notably unique feature of BTX is its relatively common therapeutic use in treating dystonia and spasticity disorders, as well as in inducing muscular atrophy despite being

12540-464: The month of March. It was recognized that the most poisonous parts were the liver and eggs, but that toxicity could be reduced by soaking the eggs. (Tetrodotoxin is slightly water-soluble, and soluble at 1 mg/ml in slightly acidic solutions.) The German physician Engelbert Kaempfer , in his "A History of Japan" (translated and published in English in 1727), described how well known the toxic effects of

12672-399: The more common in vivo systems of the past. Examples of improvements include tractable, uniform environments, and the elimination of contaminating effects of systemic metabolism. In vitro systems, however, have presented problems as it has been difficult to properly replicate the complexities of the nervous system, such as the interactions between supporting astrocytes and neurons in creating

12804-632: The most poisonous substance known. BTX functions peripherally to inhibit acetylcholine (ACh) release at the neuromuscular junction through degradation of the SNARE proteins required for ACh vesicle-membrane fusion . As the toxin is highly biologically active, an estimated dose of 1μg/kg body weight is sufficient to induce an insufficient tidal volume and resultant death by asphyxiation . Due to its high toxicity, BTX antitoxins have been an active area of research. It has been shown that capsaicin (active compound responsible for heat in chili peppers ) can bind

12936-411: The most potent neurotoxins ever discovered. MeHg is usually acquired through consumption of seafood , as it tends to concentrate in organisms high on the food chain. It is known that the mercuric ion inhibits amino acid (AA) and glutamate (Glu) transport, potentially leading to excitotoxic effects. Investigations into anatoxin- a , also known as "Very Fast Death Factor", began in 1961 following

13068-408: The muscarinic acetylcholine antagonist atropine (which will inhibit parasympathetic activity), however, can increase sympathetic nerve activity enough to improve the chance of survival after TTX exposure. Tetraethylammonium (TEA) is a compound that, like a number of neurotoxins, was first identified through its damaging effects to the nervous system and shown to have the capacity of inhibiting

13200-425: The nervous system, a number of mechanisms through which they function are through the inhibition of neuron cellular processes. These inhibited processes can range from membrane depolarization mechanisms to inter-neuron communication . By inhibiting the ability for neurons to perform their expected intracellular functions, or pass a signal to a neighboring cell, neurotoxins can induce systemic nervous system arrest as in

13332-453: The newt. Toxin-resistant garter snakes are the only known animals today that can eat a rough-skinned newt and survive. In evolutionary theory, the relationship between the rough-skinned newt and the common garter snake is considered an example of co-evolution . The mutations in the snake's genes that conferred resistance to the toxin have resulted in a selective pressure that favors newts which produce more potent levels of toxin. Increases in

13464-416: The newts. Successful predation of the rough-skinned newt by the common garter snake is made possible by the ability of individuals in a common garter snake population to gauge whether the newt's level of toxin is too high to feed on. T. sirtalis assays toxin levels of the rough-skinned newt and decides whether or not the levels are manageable by partially swallowing the newt, and either swallowing or releasing

13596-515: The past the characterization has meant poisons used by South American tribes on arrows or darts , though it has matured to specify a specific categorization of poisons which act on the neuromuscular junction to inhibit signaling and thus induce muscle relaxation. The neurotoxin category contains a number of distinct poisons, though all were originally purified from plants originating in South America. The effect with which injected curare poison

13728-401: The persistence of neurons through an individual's lifetime, leading to compounding of damages. As a result, the nervous system has a number of mechanisms designed to protect it from internal and external assaults, including the blood brain barrier. The blood–brain barrier (BBB) is one critical example of protection which prevents toxins and other adverse compounds from reaching the brain. As

13860-420: The poison has worn off. Alpha adrenergic agonists are recommended in addition to intravenous fluids to increase the blood pressure; anticholinesterase agents "have been proposed as a treatment option but have not been tested adequately". No antidote has been developed and approved for human use, but a primary research report (preliminary result) indicates that a monoclonal antibody specific to tetrodotoxin

13992-454: The poisoning of several workers in Chinese electronics factories in recent years. MPP , the toxic metabolite of MPTP is a selective neurotoxin which interferes with oxidative phosphorylation in mitochondria by inhibiting complex I , leading to the depletion of ATP and subsequent cell death. This occurs almost exclusively in dopaminergic neurons of the substantia nigra , resulting in

14124-399: The potential toxicity of using aluminium in packaging and cooking appliances. Mercury is capable of inducing CNS damage by migrating into the brain by crossing the BBB. Mercury exists in a number of different compounds, though methylmercury (MeHg ), dimethylmercury and diethylmercury are the only significantly neurotoxic forms. Diethylmercury and dimethylmercury are considered some of

14256-474: The presence of the toxin by chemical analysis, and the association of the bacteria with TTX production by toxicity assay of media in which suspected bacteria are grown. As Lago et al. note, "there is good evidence that uptake of bacteria producing TTX is an important element of TTX toxicity in marine animals that present this toxin." TTX-producing bacteria include Actinomyces , Aeromonas , Alteromonas , Bacillus , Pseudomonas , and Vibrio species; in

14388-419: The presentation of permanent parkinsonism in exposed subjects 2–3 days after administration. Unlike most common sources of neurotoxins which are acquired by the body through ingestion, endogenous neurotoxins both originate from and exert their effects in-vivo . Additionally, though most venoms and exogenous neurotoxins will rarely possess useful in-vivo capabilities, endogenous neurotoxins are commonly used by

14520-399: The receptor, acetylcholine . Once it has triggered a contraction, anatoxin- a does not allow the neurons to return to their resting state, because it is not degraded by cholinesterase which normally performs this function. As a result, the muscle cells contract permanently, the communication between the brain and the muscles is disrupted and breathing stops. When it was first discovered,

14652-426: The remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. In hindsight, it is clear that the crew survived a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus being fatally poisoned. The toxin was first isolated and named in 1909 by Japanese scientist Dr. Yoshizumi Tahara. It

14784-420: The respective manga and anime adaptations, fugu toxin is encountered across multiple mystery arcs. Based on the presumption that tetrodotoxin is not always fatal, but at near-lethal doses can leave a person extremely unwell with the person remaining conscious, tetrodotoxin has been alleged to result in zombieism , and has been suggested as an ingredient in Haitian Vodou preparations. This idea first appeared in

14916-403: The rest of the body. TTX and its analogs have historically been important agents for use as chemical tool compounds, for use in channel characterization and in fundamental studies of channel function. The prevalence of TTX-s Na channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture . The biosynthetic route to TTX

15048-422: The separate-route theory. In 2021, the first genome of a TTX-producing bacterium was produced. This " Bacillus sp. 1839" was identified as Cytobacillus gottheilii using its rRNA sequence. The researcher responsible for this study has not yet identified a coherent pathway but hopes to do so in the future. Animals that accumulate TTX as a defense mechanism as well as their predators must evolve to be resistant to

15180-435: The sodium channel – was shown definitively in 1964 by Toshio Narahashi and John W. Moore at Duke University , using the sucrose gap voltage clamp technique. Apart from their bacterial species of most likely ultimate biosynthetic origin (see below), tetrodotoxin has been isolated from widely differing animal species, including: Tarichatoxin was shown to be identical to TTX in 1964 by Mosher et al., and

15312-539: The sodium current that drives the depolarization phase of neuron action potentials . TTX-resistant (TTX-r) is another form of sodium channel which has limited sensitivity to TTX, and is largely found in small diameter axons such as those found in nociception neurons . When a significant level of TTX is ingested, it will bind sodium channels on neurons and reduce their membrane permeability to sodium. This results in an increased effective threshold of required excitatory signals in order to induce an action potential in

15444-401: The spinal cord after entering through endocytosis . This results in a loss of function in inhibitory neurons within the CNS resulting in systemic muscular contractions . Similar to the prognosis of a lethal dose of BTX, TeNT leads to paralysis and subsequent suffocation . Neurotoxic behavior of Aluminium is known to occur upon entry into the circulatory system , where it can migrate to

15576-532: The structure of tetrodotoxin. The structure was confirmed by X-ray crystallography in 1970. Yoshito Kishi and coworkers reported the first total synthesis of racemic tetrodotoxin in 1972. M. Isobe and coworkers and J. Du Bois reported the asymmetric total synthesis of tetrodotoxin in 2003. The two 2003 syntheses used very different strategies, with Isobe's route based on a Diels-Alder approach and Du Bois's work using C–H bond activation . Since then, methods have rapidly advanced, with several new strategies for

15708-432: The study of neuron response contributions of other ion channels such as voltage gated sodium channels. In addition to its many uses in neuroscience research, TEA has been shown to perform as an effective treatment of Parkinson's disease through its ability to limit the progression of the disease. Chlorotoxin (Cltx) is the active compound found in scorpion venom, and is primarily toxic because of its ability to inhibit

15840-421: The synthesis of tetrodotoxin having been developed. TTX is extremely toxic. The material safety data sheet for TTX lists the oral median lethal dose ( LD 50 ) for mice as 334  μg per kg. For comparison, the oral LD 50 of potassium cyanide for mice is 8,500 μg per kg, demonstrating that even orally, TTX is more poisonous than cyanide . TTX is even more dangerous if administered intravenously;

15972-434: The tetrodotoxin produced in the newt's skin. While in principle the toxin binds to a tube-shaped protein that acts as a sodium channel in the snake's nerve cells, researchers have identified a genetic disposition in several snake populations where the protein is configured in such a way as to hamper or prevent binding of the toxin. In each of these populations, the snakes exhibit resistance to the toxin and successfully prey upon

16104-499: The toxic effects of ammonia on astrocyte remodeling can be reduced through administration of L-carnitine . This astrocyte remodeling appears to be mediated through ammonia-induced mitochondrial permeability transition. This mitochondrial transition is a direct result of glutamine activity a compound which forms from ammonia in-vivo. Administration of antioxidants or glutaminase inhibitor can reduce this mitochondrial transition, and potentially also astrocyte remodeling. Arsenic

16236-430: The toxin acts as a defense mechanism, some predators such as the common garter snake have developed insensitivity to TTX, which allows them to prey upon toxic newts . The association of TTX with consumed, infecting, or symbiotic bacterial populations within the animal species from which it is isolated is relatively clear; presence of TTX-producing bacteria within an animal's microbiome is determined by culture methods,

16368-403: The toxin in any preparation. Discussion of the matter has therefore all but disappeared from the primary literature since the early 1990s. Kao and Yasumoto concluded in the first of their papers in 1986 that "the widely circulated claim in the lay press to the effect that tetrodotoxin is the causal agent in the initial zombification process is without factual foundation." Genetic background is not

16500-539: The toxin was called the Very Fast Death Factor (VFDF) because when it was injected into the body cavity of mice it induced tremors, paralysis and death within a few minutes. In 1977, the structure of VFDF was determined as a secondary, bicyclic amine alkaloid , and it was renamed anatoxin- a . Structurally, it is similar to cocaine. There is continued interest in anatoxin- a because of the dangers it presents to recreational and drinking waters, and because it

16632-560: The treatment of cancer-related pain in phase II and III clinical trials. Tetrodotoxin is a sodium channel blocker . It inhibits the firing of action potentials in neurons by binding to the voltage-gated sodium channels in nerve cell membranes and blocking the passage of sodium ions (responsible for the rising phase of an action potential) into the neuron. This prevents the nervous system from carrying messages and thus muscles from contracting in response to nervous stimulation. Its mechanism of action – selective blocking of

16764-422: The two compounds is that while BTX inhibits muscular contractions , TeNT induces them. Though both toxins inhibit vesicle release at neuron synapses, the reason for this different manifestation is that BTX functions mainly in the peripheral nervous system (PNS) while TeNT is largely active in the central nervous system (CNS). This is a result of TeNT migration through motor neurons to the inhibitory neurons of

16896-407: The unique forms of conotoxins, ω-conotoxin ( ω-CgTx ) is highly specific for Ca channels and has shown usefulness in isolating them from a system. As calcium flux is necessary for proper excitability of a cell, any significant inhibition could prevent a large amount of functionality. Significantly, ω-CgTx is capable of long term binding to and inhibition of voltage-dependent calcium channels located in

17028-404: The unique traits of individuals. As with any highly complex system, however, even small perturbations to its environment can lead to significant functional disruptions. Properties leading to the susceptibility of nervous tissue include a high surface area of neurons, a high lipid content which retains lipophilic toxins, high blood flow to the brain inducing increased effective toxin exposure, and

17160-405: The unmutated VGSC. Another path to TTX resistance is toxin-binding proteins that hold onto TTX tightly enough to prevent it reaching the vulnerable VGSCs. Various proteins that bind TTX have been found in pufferfish, crabs, and gastropods. There are also proteins that bind saxitoxin (STX), a toxin with a similar mode of action. In 1964, a team of scientists led by Robert B. Woodward elucidated

17292-582: Was also interrupted for a time. After exhaustive analysis, it was found that the sea slugs must have ingested tetrodotoxin. Statistics from the Tokyo Bureau of Social Welfare and Public Health indicate 20–44 incidents of fugu poisoning per year between 1996 and 2006 in the entire country, leading to 34–64 hospitalizations and 0–6 deaths per year, for an average fatality rate of 6.8%. Of the 23 incidents recorded within Tokyo between 1993 and 2006, only one took place in

17424-449: Was one of the agents studied by Japan's Unit 731 , which evaluated biological weapons on human subjects in the 1930s. The diagnosis of pufferfish poisoning is based on the observed symptomatology and recent dietary history. Symptoms typically develop within 30 minutes of ingestion, but may be delayed by up to four hours; however, if the dose is fatal, symptoms are usually present within 17 minutes of ingestion. Having pins and needles of

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