neurotoxin neurotoxin 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. though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. common examples of neurotoxins include lead, ethanol (drinking alcohol), glutamate, nitric oxide, botulinum toxin (e.g. botox), tetanus toxin, and tetrodotoxin. some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations. not to be confused with nerve agent. 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 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 is common. support has been shown for a number of treatments aimed at attenuating neurotoxin-mediated injury, such as antioxidant and antitoxin administration. background 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 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 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. astrocytes surrounding capillaries in the brain to form the blood brain barrier 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 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. choroid plexus by being hydrophobic and small, or inhibiting astrocyte function, some compounds including certain neurotoxins are able to penetrate into 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 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 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 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 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 ddt 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. likewise through isolation of certain channel activities, neurotoxins have provided 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. mechanisms of activity as neurotoxins are compounds which adversely affect 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 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. 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, mercury receptor inhibitors/antagonists bungarotoxin, curare receptor agonists anatoxin-a, caramboxin, 25i-nbome, jwh-018, 5-meo-dipt cytoskeleton interference ammonia, arsenic ca-mediated cytotoxicity lead multiple effects ethanol, n-hexane, methanol receptor-selective neurotoxins mpp+ endogenous neurotoxin sources nitric oxide, glutamate, dopamine tetrodotoxin 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 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 the sodium current that drives the depolarization phase of neuron action potentials. inhibited signaling response resulting from neuron exposure to tetrodotoxin. 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 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 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 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 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 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 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 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. 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