Neurotoxin - WikiHQ

thumb|300px|right|Neurotoxins can be found in a number of organisms, including some strains of [[cyanobacteria, that can be found in algal blooms or washed up on shore in a green scum.]]

Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. ethanol (drinking alcohol), glutamate, nitric oxide, botulinum toxin (e.g. Botox), tetanus toxin, and tetrodotoxin. 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, epilepsy, and dementia. Additionally, neurotoxin-mediated peripheral nervous system damage such as neuropathy or myopathy is common. Support has been shown for a number of treatments aimed at attenuating neurotoxin-mediated injury, such as antioxidant administration.

Background

thumb|upright=1.5|alt=Complete labeled neuron.|Illustration of typical multipolar neuron

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 the development of extensive plumbing networks and the habit of boiling vinegared wine in lead pans to sweeten it. The process generates 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 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 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 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 a number of potential chemical insults. 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. Though clinical neurotoxicology is largely a burgeoning field, extensive inroads have been made in the identification of many environmental neurotoxins leading to the classification of 750 to 1000 known potentially neurotoxic compounds. 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 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 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.

Applications in neuroscience

Though diverse in chemical properties and functions, neurotoxins share the common property that they act by some mechanism leading to either 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 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. 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

{|| class="wikitable"

! Neurotoxin classification

! Neurotoxins

|Na channel inhibitors

|Tetrodotoxin

|K channel inhibitors

|Tetraethylammonium

|Cl channel inhibitors

|Chlorotoxin,

|Ca channel inhibitors

|Conotoxin

|Inhibitors of synaptic vesicle release

|Botulinum toxin,

Tetanus toxin

|Blood brain barrier inhibitors

|Aluminium,

|Receptor inhibitors/antagonists

|Bungarotoxin,

Curare

|Receptor agonists

|Anatoxin-a,

JWH-018,

5-MEO-DiPT

|Cytoskeleton interference

|Ammonia,

Arsenic

|Ca-mediated cytotoxicity

|Lead

|Protein misfolding

|Tau protein

|Multiple effects

|Ethanol,

N-Hexane,

Glutamate,

Dopamine

Inhibitors

Sodium channel

Tetrodotoxin

thumb|alt=Puffer Fish.|The [[puffer fish is known for carrying lethal amounts of tetrodotoxin.]]

Tetrodotoxin (TTX) 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 the mouth and limbs), muscle weakness, nausea, and vomiting 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 the sodium current that drives the depolarization phase of neuron action potentials. Additionally, through chronic TEA administration, muscular atrophy would be induced. 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.

Chloride channel

Chlorotoxin

Chlorotoxin (Cltx) is the active compound found in scorpion venom, and is primarily toxic because of its ability to inhibit the conductance of chloride channels.

Calcium channel

Conotoxin

Conotoxins represent 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. 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 the membranes of neurons but not those of muscle cells.

Synaptic vesicle release

Botulinum toxin

thumb|alt=Mechanism of Botulinum Toxin neurotoxicity.|Mechanism of Botulinum Toxin neurotoxicity 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, This is a result of TeNT migration through motor neurons to the inhibitory neurons of 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. 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 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 the potential toxicity of using aluminium in packaging and cooking appliances.

Mercury

Mercury is capable of inducing CNS damage by migrating into the brain by crossing the BBB. It is known that the mercuric ion inhibits amino acid (AA) and glutamate (Glu) transport, potentially leading to excitotoxic effects.

Receptor agonists and antagonists

Anatoxin-a

Investigations into anatoxin-a, also known as "Very Fast Death Factor", began in 1961 following 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-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 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, 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 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

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 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. 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.

Caramboxin

thumb|140px|right|class=skin-invert-image|[[Caramboxin]]

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 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.

Curare

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 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. 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.

Cytoskeleton interference

Ammonia

thumb|alt=Astrocyte.|An Astrocyte, a cell notable for maintaining the blood brain barrier

Ammonia toxicity 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 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. Administration of antioxidants or glutaminase inhibitor can reduce this mitochondrial transition, and potentially also astrocyte remodeling. 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 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. Additionally, similar to other neurotoxin treatments, the administration of certain antioxidants has shown some promise in reducing neurotoxicity of ingested arsenic. 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. 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.

Neurotoxins with multiple effects

Ethanol

thumb|alt=Image of Fetal Alcohol Syndrome|Male baby exhibiting [[Fetal Alcohol Syndrome (FAS).]]

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 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. 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 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 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 a result of increased generation of reactive oxidative species (ROS). In support of this mechanism, administration of high levels of dietary vitamin E results in reduced or eliminated ethanol-induced neurotoxic effects in fetuses.

Receptor-selective neurotoxins

MPP<sup>+</sup>

MPP<sup>+</sup>, 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 the presentation of permanent parkinsonism in exposed subjects 2–3 days after administration.

Endogenous neurotoxin sources

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 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. inducing DNA damage and apoptosis. Thus an increased presence of NO in an ischemic area of the CNS can produce significantly toxic effects.

Glutamate

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.