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Neurotoxins are
toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...
s that are destructive to
nerve tissue Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain ...
(causing
neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
). Neurotoxins are an extensive class of exogenous chemical
neurological Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the s ...
insults An insult is an expression, statement, or behavior that is often deliberately disrespectful, offensive, scornful, or derogatory towards an individual or a group. Insults can be intentional or unintentional, and they often aim to belittle, off ...
Spencer 2000 that can adversely affect function in both developing and mature nervous tissue.Olney 2002 The term can also be used to classify
endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
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 Lead () is a chemical element; it has Chemical symbol, symbol Pb (from Latin ) and atomic number 82. It is a Heavy metal (elements), heavy metal that is density, denser than most common materials. Lead is Mohs scale, soft and Ductility, malleabl ...
,
ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
(drinking alcohol),
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
,Choi 1987
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
,
botulinum toxin Botulinum toxin, or botulinum neurotoxin (commonly called botox), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon en ...
(e.g. Botox),
tetanus toxin Tetanus toxin (TeNT) is an extremely potent neurotoxin produced by the vegetative cell of '' Clostridium tetani'' in anaerobic conditions, causing tetanus. It has no known function for clostridia in the soil environment where they are normal ...
,Simpson 1986 and
tetrodotoxin Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an Order (biology), order that includes Tetraodontidae, pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Alt ...
. Some substances such as
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
and
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations. Neurotoxins inhibit
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
control over
ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
concentrations across the cell membrane, or communication between neurons across a
synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
.Arnon 2001 Local
pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
of neurotoxin exposure often includes neuron
excitotoxicity In excitotoxicity, neuron, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamic acid, glutamate become pathologically high, resulting in excessive stimulation of cell surface recept ...
or
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
Dikranian 2001 but can also include
glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...
damage.Deng 2003 Macroscopic manifestations of neurotoxin exposure can include widespread
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
damage such as
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
, persistent
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...
impairments,
epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
, and
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
. Additionally, neurotoxin-mediated
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
damage such as
neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
or
myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...
is common. Support has been shown for a number of treatments aimed at attenuating neurotoxin-mediated injury, such as
antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
and
antitoxin An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacterium, bacteria in response to toxin exposure. Although they are most effective in neutralizing toxins, the ...
Thyagarajan 2009 administration.


Background

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 The Roman Empire ruled the Mediterranean and much of Europe, Western Asia and North Africa. The Roman people, Romans conquered most of this during the Roman Republic, Republic, and it was ruled by emperors following Octavian's assumption of ...
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 Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
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 The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
,
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
, 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 Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
content which retains lipophilic toxins, high
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...
flow to the brain inducing increased effective toxin exposure, and the persistence of neurons through an individual's lifetime, leading to compounding of damages.Dobbs 2009 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 The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
(BBB) is one critical example of protection which prevents toxins and other adverse compounds from reaching the brain.Widmaier, Eric P., Hershel Raff, Kevin T. Strang, and Arthur J. Vander (2008) Vander's Human Physiology: the Mechanisms of Body Function.' Boston: McGraw-Hill Higher Education. 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
astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
s 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. This barrier creates a tight
hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
layer around the
capillaries A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima (the in ...
in the brain, inhibiting the transport of large or
hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...
compounds. In addition to the BBB, the
choroid plexus The choroid plexus, or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. Regions of the choroid plexus produce and secrete most of the cerebrospinal fluid (CSF) of the central ...
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 The ependyma is the thin neuroepithelial ( simple columnar ciliated epithelium) lining of the ventricular system of the brain and the central canal of the spinal cord. The ependyma is one of the four types of neuroglia in the central nervous sys ...
cells, are responsible for the synthesis of
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
(CSF).Martini 2009 Importantly, through selective passage of
ions An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
and nutrients and trapping
heavy metals upright=1.2, Crystals of lead.html" ;"title="osmium, a heavy metal nearly twice as dense as lead">osmium, a heavy metal nearly twice as dense as lead Heavy metals is a controversial and ambiguous term for metallic elements with relatively h ...
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 the brain and induce significant damage. In modern times,
scientist A scientist is a person who Scientific method, researches to advance knowledge in an Branches of science, area of the natural sciences. In classical antiquity, there was no real ancient analog of a modern scientist. Instead, philosophers engag ...
s and
physician A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...
s 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.Costa 2011 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 The Environmental Protection Agency (EPA) is an independent agency of the United States government tasked with environmental protection matters. President Richard Nixon proposed the establishment of EPA on July 9, 1970; it began operation on De ...
(EPA) for testing and determining neurotoxic effects of compounds (USEPA 1998). Additionally,
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
systems have increased in use as they provide significant improvements over the more common
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
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 Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
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 Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
or
skeletal A skeleton is the structural frame that supports the body of most animals. There are several types of skeletons, including the exoskeleton, which is a rigid outer shell that holds up an organism's shape; the endoskeleton, a rigid internal fram ...
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
cytotoxin Cytotoxicity is the quality of being toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium ...
s 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 Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...
capacity of
organophosphate In organic chemistry, organophosphates (also known as phosphate esters, or OPEs) are a class of organophosphorus compounds with the general structure , a central phosphate molecule with alkyl or aromatic substituents. They can be considered ...
s (includes
parathion Parathion, also called parathion-ethyl or diethyl parathion, is an organophosphate insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, including humans, so its use has been ...
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 In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...
. Neurotoxins, however, by their very design can be very useful in the field of
neuroscience Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions, and its disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, ...
. 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 targetsAdams 2003 (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 channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...
s 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 channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of ...
s could account for most nervous tissue function. From this basic understanding, the use of common compounds such as tetrodotoxin,
tetraethylammonium Tetraethylammonium (TEA) is a quaternary ammonium cation with the chemical formula , consisting of four ethyl groups (, denoted Et) attached to a central nitrogen atom. It is a counterion used in the research laboratory to prepare lipophilic salt ...
, 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 Botulinum toxin, or botulinum neurotoxin (commonly called botox), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon en ...
, or even nervous tissue death.Brocardo 2011 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.


Inhibitors


Sodium channel


=Tetrodotoxin

=
Tetrodotoxin Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an Order (biology), order that includes Tetraodontidae, pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Alt ...
(TTX) is a poison produced by organisms belonging to the Tetraodontiformes order, which includes the puffer fish,
ocean sunfish The ocean sunfish (''Mola mola''), also known as the common mola, is one of the largest bony fish in the world. It is the type species of the genus ''Mola'', and one of five extant species in the family Molidae. It was once misidentified as th ...
, and porcupine fish. Within the puffer fish, TTX is found in the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
gonads A gonad, sex gland, or reproductive gland is a mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, ...
,
intestines The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...
, and
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...
. TTX can be fatal if consumed, and has become a common form of poisoning in many countries. Common symptoms of TTX consumption include
paraesthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or chronic and has many possible underlying causes. Paresthesia is usually painless and can oc ...
(often restricted to the
mouth A mouth also referred to as the oral is the body orifice through which many animals ingest food and animal communication#Auditory, vocalize. The body cavity immediately behind the mouth opening, known as the oral cavity (or in Latin), is also t ...
and limbs), muscle weakness,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
, and
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
and often manifest within 30 minutes of
ingestion Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in a substance through the mouth into the gastrointestinal tract, such as through eating or drinking. In single-celled organisms, inge ...
. 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 potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
s. 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 Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of n ...
or the muscarinic acetylcholine antagonist
atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically give ...
(which will inhibit parasympathetic activity), however, can increase sympathetic nerve activity enough to improve the chance of survival after TTX exposure.


Potassium channel


=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 muscular system, musculature in a manner similar to that of curare.Standfield 1983 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 outward potassium current, delayed rectifier seen in an
action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
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.


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. 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.


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.Jacob 2010 In many cases, the toxins released by the different types of Coninae, 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 the unique forms of conotoxins, ω-conotoxin (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 the membranes of neurons but not those of muscle cells.


Synaptic vesicle release


=Botulinum toxin

= 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.Brin, Mitchell F (1997) "Botulinum Toxin: Chemistry, Pharmacology, Toxicity, and Immunology." ''Muscle & Nerve,'' 20 (S6): 146–68. 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 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 (biology and chemistry), 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 the TRPV1, TRPV1 receptor expressed on cholinergic, cholinergic neurons and inhibit the toxic effects of BTX.


=Tetanus toxin

= Tetanus, 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 clostridium tetani, clostridial neurotoxins. Like BTX, TeNT inhibits inter-neuron communication by means of vesicular neurotransmitter (NT) release. One notable difference between the two compounds is that while BTX inhibits muscle, 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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS). This is a result of TeNT migration through motor neurons to the inhibitory neurotransmitter, inhibitory neurons of the spinal cord after entering through endocytosis.Pirazzini 2011 This results in a loss of function in inhibitory neurons within the CNS resulting in systemic muscle contraction, muscular contractions. Similar to the prognosis of a lethal dose of BTX, TeNT leads to paralysis and subsequent suffocation.


Blood brain barrier


=Aluminium

= Neurotoxic behavior of aluminium (element), Aluminium is known to occur upon entry into the circulatory system, where it can migrate to the brain and inhibit some of the crucial functions of the blood brain barrier (BBB).Banks 1988 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 (element), 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 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 Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
(Glu) transport, potentially leading to excitotoxic effects.


Receptor agonists and antagonists


Anatoxin-a

Investigations into Anatoxin-a, 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.Carmichael 1978Carmichael 1975 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 (
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s). The progressive symptoms of anatoxin-''a'' exposure are loss of coordination, Fasciculation, twitching, convulsions and rapid death by respiratory paralysis. The nerve tissues which communicate with muscles contain a Receptor (biochemistry), 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 Intraperitoneal injection, 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.Metcalf 2009 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.Stewart 2008 The deadliness of the toxin means that it has a high military potential as a toxin weapon.Dixit 2005


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.Tsetlin 2003 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, 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 is particularly specific for alpha-7 nicotinic receptor, α7-nAChR.Liu 2008 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 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

= Caramboxin (CBX) is a
toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...
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 receptor, NMDA and AMPA receptor, 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 indigenous peoples of the americas, South American tribes on arrows or dart (missile), 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.Bisset 1992 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 is usually associated is muscle paralysis and resultant death.Schlesinger 1946 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

Ammonia toxicity is often seen through two routes of administration, either through consumption or through endogenous ailments such as liver failure.Matsuoka 1991 One notable case in which ammonia toxicity is common is in response to cirrhosis of the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
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 cyclic guanosine monophosphate, cGMP (Cyclic Guanosine Monophosphate) within the cells which leads to cGMP-dependent protein kinase, Protein Kinase G-mediated (PKG) cytoskeletal modifications. The resultant effect of this toxicity can be reduced brain energy metabolism and function. Importantly, the toxic effects of ammonia on astrocyte remodeling can be reduced through administration of carnitine, 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.Norenberg 2004 Administration of
antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
s or glutaminase inhibitor can reduce this mitochondrial transition, and potentially also astrocyte remodeling.


Arsenic

Arsenic 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 neuronal migration, neural migration, and significant morphological changes of neurons during developmental biology, development,Rocha 2011) often leading to neural tube defects in infant, 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. Another known function of arsenite 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.


Calcium-mediated cytotoxicity


Lead

Lead is a potent neurotoxin whose toxicity has been recognized for at least thousands of years.Lidskey 2003 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 Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
and excitotoxicity. An underlying mechanism by which lead is able to cause harm is its ability to be transported by atpase, calcium ATPase pumps across 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 a result of early lead exposure. In addition to inducing apoptosis, lead inhibits interneuron signaling through the disruption of calcium-mediated neurotransmitter release.


Neurotoxins with multiple effects


Ethanol

As a neurotoxin,
ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
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. 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 is the ability for ethanol to inhibit nmda receptor, 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 pathway, mesolimbic dopamine neurons in an inositol triphosphate, 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.Takadera 1990 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 system, 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, 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 oxygen species, 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 diet (nutrition), dietary vitamin E results in reduced or eliminated ethanol-induced neurotoxic effects in fetuses.


n-Hexane

n-Hexane is a neurotoxin which has been responsible for the poisoning of several workers in Chinese electronics factories in recent years.Occupational Safety and Health Guideline for n-Hexane
, OSHA.gov


Receptor-selective neurotoxins


MPP+

MPP+, 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 Adenosine triphosphate, 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, 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.


Nitric oxide

Though
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
(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 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 Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, inducing DNA damage and apoptosis.Bonfoco 1995 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. 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 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 Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
, and stroke.


See also

*Babycurus toxin 1 *Cangitoxin *Chronic solvent-induced encephalopathy *Fertilizer *Herbicide *Pesticides *Solvent *Toxic encephalopathy


Notes


References

* * * * * * * * * * * * * * * * * * * * * Chan, H. M. (2011) "Mercury in Fish: Human Health Risks." ''Encyclopedia of Environmental Health'': 697–704. * * * * * * * Costa, Lucio G., Gennaro Giordano, and Marina Guizzetti (2011) ''In Vitro Neurotoxicology: Methods and Protocols.'' New York: Humana. * * * * * Debin, John A., John E. Maggio, and Gary R. Strichartz (1993) "Purification and Characterization of Chlorotoxin, a Chloride Channel Ligand from the Venom of the Scorpion." ''The American Physiological Society'', pp. 361–69. * * Defuria, Jason (2006) "The Environmental Neurotoxin Arsenic Impairs Neurofilament Dynamics by Overactivation of C-JUN Terminal Kinase: Potential Role for Amyotrophic Lateral Sclerosis." ''UMI'', pp. 1–16. * * * * * * Dobbs, Michael R (2009) ''Clinical Neurotoxicology.'' Philadelphia: Saunders-Elsevier. * * * * * * * * * * Herbert, M. R. (2006) "Autism and Environmental Genomics." ''NeuroToxicology'', pp. 671–84. Web. * Hodge, A. Trevor (2002) ''Roman Aqueducts and Water Supply''. London: Duckworth. * * * * * * * * * * * * * * * * * * Lotti, Marcello, and Angelo Moretto (1989) "Organophosphate-Induced Delayed Polyneuropathy." ''Toxicological Reviews,'' 24 (1) (2005): 37–49. * * Martini, Frederic, Michael J. Timmons, and Robert B. Tallitsch (2009) ''Human Anatomy.'' San Francisco: Pearson/Benjamin Cummings. * * * * * * * * Morris, Stephanie A., David W. Eaves, Aleksander R. Smith, and Kimberly Nixon (2009) "Alcohol Inhibition of Neurogenesis: A Mechanism of Hippocampal Neurodegeneration in an Adolescent Alcohol Abuse Model." Hippocampus: NA. * * National Center for Environmental Assessment (2006) "Toxicological Reviews of Cyanobacterial Toxins: Anatoxin-a" NCEA-C-1743 * * * * Pirazzini, Marco, Ornella Rossetto, Paolo Bolognese, Clifford C. Shone, and Cesare Montecucco (2011) "Double Anchorage to the Membrane and Intact Inter-chain Disulfide Bond Are Required for the Low PH Induced Entry of Tetanus and Botulinum Neurotoxins into Neurons." Cellular Microbiology: No. Print. * * * * * * * * * Spencer PS, Schaumburg HH, Ludolph AC (Eds) (2000) Experimental and Clinical Neurotoxicology. Oxford University Press, Oxford, pp. 1310. * * * * * * * * USEPA (United States Environmental Protection Agency) (1998) Health Effects Test Guidelines. OPPTS 870.6200. Neurotoxicity screening battery. Washington DC, USEPA. * Vahidnia, A., G.B. Van Der Voet, and F.A. De Wolff (2007) "Arsenic Neurotoxicity A Review." ''Human & Experimental Toxicology,'' 26 (10) : 823–32. * * Widmaier, Eric P., Hershel Raff, Kevin T. Strang, and Arthur J. Vander (2008) ''Vander's Human Physiology: the Mechanisms of Body Function.'' Boston: McGraw-Hill Higher Education. * * * * * Yang, X (2007
''Occurrence of the cyanobacterial neurotoxin, anatoxin-a, in New York State waters''
ProQuest. . *


Further reading


Brain Facts Book
at The Society for Neuroscience
Neuroscience Texts
at University of Texas Medical School
In Vitro Neurotoxicology: An Introduction
at Springerlink
Biology of the NMDA Receptor
at NCBI
Advances in the Neuroscience of Addiction, 2nd edition
at NCBI


External links


Environmental Protection Agency
at United States Environmental Protection Agency
Alcohol and Alcoholism
at Oxford Medical Journals
Neurotoxins
at Toxipedia {{Cyanotoxins Neurotoxins,