Neurotoxins aretoxins that are destructive tonerve tissue (causingneurotoxicity).[3] Neurotoxins are an extensive class ofexogenous chemicalneurologicalinsults[4] that can adversely affect function in both developing and mature nervous tissue.[5] The term can also be used to classifyendogenous compounds, which, when abnormally contacted, can prove neurologically toxic.[4] Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems.[6] Common examples of neurotoxins includelead,[7]ethanol (drinking alcohol),[8]glutamate,[9]nitric oxide,[10]botulinum toxin (e.g. Botox),[11]tetanus toxin,[12] andtetrodotoxin.[6] Some substances such asnitric oxide andglutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.
Neurotoxins inhibitneuron control overion concentrations across thecell membrane,[6] or communication between neurons across asynapse.[13] Localpathology of neurotoxin exposure often includes neuronexcitotoxicity orapoptosis[14] but can also includeglial cell damage.[15] Macroscopic manifestations of neurotoxin exposure can include widespreadcentral nervous system damage such asintellectual disability,[5] persistentmemory impairments,[16]epilepsy, anddementia.[17] Additionally, neurotoxin-mediatedperipheral nervous system damage such asneuropathy ormyopathy is common. Support has been shown for a number of treatments aimed at attenuating neurotoxin-mediated injury, such asantioxidant[8] andantitoxin[18] administration.
Exposure to neurotoxins in society is not new,[19] as civilizations have been exposed to neurologically destructive compounds for thousands of years. One notable example is the possible significant lead exposure during theRoman Empire resulting from the development of extensiveplumbing networks and the habit of boiling vinegared wine in lead pans to sweeten it. The process generateslead acetate, known as "sugar of lead".[20] In part, neurotoxins have been part ofhuman history because of the fragile and susceptible nature of the nervous system, making it highly prone to disruption.
The nervous tissue found in thebrain,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 highlipid content which retains lipophilic toxins, highblood flow to the brain inducing increased effective toxin exposure, and the persistence of neurons through an individual's lifetime, leading to compounding of damages.[21] 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.
Theblood–brain barrier (BBB) is one critical example of protection which prevents toxins and other adverse compounds from reaching the brain.[22] 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 termedastrocytes 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.[22]
This barrier creates a tighthydrophobic layer around thecapillaries in the brain, inhibiting the transport of large orhydrophilic compounds. In addition to the BBB, thechoroid 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 lateralventricles of the brain, which through the function of theirependymal cells, are responsible for the synthesis ofcerebrospinal fluid (CSF).[23] Importantly, through selective passage ofions and nutrients and trappingheavy metals such as lead, the choroid plexuses maintain a strictly regulated environment which contains the brain and spinal cord.[22][23]
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 andphysicians 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.[24] 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.[21] Due to the critical importance of finding neurotoxins in common environments, specific protocols have been developed by theUnited 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 commonin vivo systems of the past. Examples of improvements include tractable, uniform environments, and the elimination of contaminating effects of systemic metabolism.[24] 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.[25] 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 ofcells to chemicals may not accurately convey a distinction between neurotoxins and cytotoxins, as symptoms likeoxidative stress orskeletal modifications may occur in response to either.[26]
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 andcytotoxins in an in-vitro testing environment. Due to the significant inaccuracies associated with this process, however, it has been slow in gaining widespread support.[27] 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 ofacetylcholinesterase capacity oforganophosphates (includesparathion andsarin gas).[28] Though methods of determining neurotoxicity still require significant development, the identification of deleterious compounds and toxin exposure symptoms has undergone significant improvement.
Though diverse in chemical properties and functions, neurotoxins share the common property that they act by some mechanism leading to either the disruption or destruction of necessary components within thenervous system. Neurotoxins, however, by their very design can be very useful in the field ofneuroscience. 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. Asvenomous 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[29] (seeIon 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 usedradiolabeled tetrodotoxin to assaysodium channels and obtain precise measurements about their concentration along nervemembranes.[29] Likewise through isolation of certain channel activities, neurotoxins have provided the ability to improve the originalHodgkin-Huxley model of the neuron in which it was theorized that single generic sodium andpotassium channels could account for most nervous tissue function.[29] From this basic understanding, the use of common compounds such as tetrodotoxin,tetraethylammonium, andbungarotoxins have led to a much deeper understanding of the distinct ways in which individual neurons may behave.
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 tointer-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 ofbotulinum toxin,[13] or even nervous tissue death.[30] 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[18] and years for lead.[31]
| Neurotoxin classification | Neurotoxins |
|---|---|
| Na channel inhibitors | Tetrodotoxin[6] |
| K channel inhibitors | Tetraethylammonium[32] |
| Cl channel inhibitors | Chlorotoxin,[33] |
| Ca channel inhibitors | Conotoxin[34] |
| Inhibitors of synaptic vesicle release | Botulinum toxin,[35] |
| Blood brain barrier inhibitors | Aluminium,[37] |
| Receptor inhibitors/antagonists | Bungarotoxin,[39] |
| Receptor agonists | Anatoxin-a,[41][42] |
| Cytoskeleton interference | Ammonia,[46] |
| Ca-mediated cytotoxicity | Lead[48] |
| Protein misfolding | Tau protein |
| Multiple effects | Ethanol,[49][50] |
| Receptor-selective neurotoxins | MPP+ |
| Endogenous neurotoxin sources | Nitric oxide,[52] |
Tetrodotoxin (TTX) is a poison produced by organisms belonging to theTetraodontiformes order, which includes thepuffer fish,ocean sunfish, andporcupine fish.[55] Within the puffer fish, TTX is found in theliver,gonads,intestines, andskin.[6][56] TTX can be fatal if consumed, and has become a common form of poisoning in many countries. Common symptoms of TTX consumption includeparaesthesia (often restricted to themouth andlimbs), muscle weakness,nausea, andvomiting[55] and often manifest within 30 minutes ofingestion.[57] 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 thedepolarization phase of neuronaction potentials.[6]
TTX-resistant (TTX-r) is another form of sodium channel which has limited sensitivity to TTX, and is largely found insmall diameter axons such as those found innociception neurons.[6] When a significant level of TTX is ingested, it will bind sodium channels on neurons and reduce theirmembrane 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.[6] The effect of this increasedsignaling threshold is a reduced excitability ofpostsynaptic neurons, and subsequent loss of motor and sensory function which can result in paralysis and death. Thoughassisted ventilation may increase the chance of survival after TTX exposure, there is currently no antitoxin. The use of the acetylcholinesterase inhibitorNeostigmine or the muscarinicacetylcholine antagonistatropine (which will inhibit parasympathetic activity), however, can increasesympathetic nerve activity enough to improve the chance of survival after TTX exposure.[55]
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 themusculature in a manner similar to that of curare.[58] Additionally, through chronic TEA administration, muscular atrophy would be induced.[58] It was later determined that TEA functions in-vivo primarily through its ability to inhibit both the potassium channels responsible for thedelayed rectifier seen in anaction potential and some population of calcium-dependent potassium channels.[32] 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.[58] What makes TEA very useful forneuroscientists 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.[59] In addition to its many uses in neuroscience research, TEA has been shown to perform as an effective treatment ofParkinson's disease through its ability to limit the progression of the disease.[60]
Chlorotoxin (Cltx) is the active compound found inscorpion venom, and is primarily toxic because of its ability to inhibit the conductance ofchloride channels.[33] 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 forgliomas to infiltrate healthy nervous tissue in the brain, significantly reducing the potential invasive harm caused by tumors.[61][62]
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.[63][64] In many cases, the toxins released by the different types ofcone 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.[63] One of the unique forms of conotoxins, ω-conotoxin (ω-CgTx) is highly specific for Ca channels and has shown usefulness in isolating them from a system.[65] 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.[66]
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 bacteriumClostridium botulinum and lead to muscularparalysis.[67] A notably unique feature of BTX is its relatively common therapeutic use in treatingdystonia andspasticity disorders,[67] as well as in inducingmuscular atrophy[11] despite being the most poisonous substance known.[18] BTX functions peripherally to inhibitacetylcholine (ACh) release at theneuromuscular junction through degradation of theSNARE proteins required for AChvesicle-membrane fusion.[35] As the toxin is highly biologically active, an estimated dose of 1μg/kg body weight is sufficient to induce an insufficient tidal volume and resultantdeath byasphyxiation.[13] Due to its high toxicity, BTX antitoxins have been an active area of research. It has been shown thatcapsaicin (active compound responsible for heat inchili peppers) can bind theTRPV1 receptor expressed oncholinergic neurons and inhibit the toxic effects of BTX.[18]
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 ofclostridial neurotoxins.[12] Like BTX, TeNT inhibits inter-neuron communication by means of vesicular neurotransmitter (NT) release.[36] One notable difference between the two compounds is that while BTX inhibitsmuscular 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 thecentral nervous system (CNS).[68] This is a result of TeNT migration throughmotor neurons to theinhibitory neurons of the spinal cord after entering throughendocytosis.[69] This results in a loss of function in inhibitory neurons within the CNS resulting in systemicmuscular contractions. Similar to theprognosis of a lethal dose of BTX, TeNT leads to paralysis and subsequentsuffocation.[69]
Neurotoxic behavior ofAluminium is known to occur upon entry into thecirculatory system, where it can migrate to the brain and inhibit some of the crucial functions of the blood brain barrier (BBB).[37] 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 themetal is known to be neurotoxic, effects are usually restricted topatients incapable of removing excess ions from the blood, such as those experiencingrenal failure.[70] Patients experiencing aluminium toxicity can exhibitsymptoms such as impaired learning and reducedmotor coordination.[71] Additionally, systemic aluminium levels are known to increase with age, and have been shown to correlate withAlzheimer's disease, implicating it as a neurotoxic causative compound of the disease.[72] Despite its known toxicity in its ionic form, studies are divided on the potential toxicity of using aluminium in packaging and cooking appliances.
Mercury is capable of inducing CNS damage by migrating into the brain by crossing the BBB.[38] Mercury exists in a number of different compounds, thoughmethylmercury (MeHg+),dimethylmercury anddiethylmercury are the only significantly neurotoxic forms. Diethylmercury and dimethylmercury are considered some of the most potent neurotoxins ever discovered.[38] MeHg+ is usually acquired through consumption ofseafood, as it tends to concentrate in organisms high on the food chain.[73] It is known that the mercuric ion inhibitsamino acid (AA) andglutamate (Glu) transport, potentially leading to excitotoxic effects.[74]
| External videos | |
|---|---|
 Very Fast Death FactorUniversity of Nottingham |
Investigations intoanatoxin-a, also known as "Very Fast Death Factor", began in 1961 following the deaths of cows that drank from a lake containing analgal bloom in Saskatchewan, Canada.[41][42] It is acyanotoxin produced by at least four different genera ofcyanobacteria, and has been reported in North America, Europe, Africa, Asia, and New Zealand.[75]
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 byrespiratory paralysis. The nerve tissues which communicate with muscles contain areceptor called thenicotinic acetylcholine receptor. Stimulation of these receptors causes amuscular contraction. The anatoxin-a molecule is shaped so it fits this receptor, and in this way it mimics the naturalneurotransmitter 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 bycholinesterase 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.[76][77]
When it was first discovered, the toxin was called the Very Fast Death Factor (VFDF) because when it wasinjected 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, bicyclicaminealkaloid, and it was renamed anatoxin-a.[78][79] Structurally, it is similar to cocaine.[80] 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.[81] The deadliness of the toxin means that it has a high military potential as a toxin weapon.[82]
Bungarotoxin is a compound with known interaction withnicotinic acetylcholine receptors (nAChRs), which constitute a family ofion channels whose activity is triggered by neurotransmitter binding.[83] 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 thebanded krait snake.[39] 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.[39] As there are multiple forms of bungarotoxin, there are different forms of nAChRs to which they will bind, and α-bungarotoxin is particularly specific forα7-nAChR.[84] This α7-nAChR functions to allowcalcium ion influx into cells, and thus when blocked by ingested bungarotoxin will produce damaging effects, as ACh signaling will be inhibited.[84] 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 andκ-bungarotoxin is specific for nAChRs found in neurons.[85]
Caramboxin (CBX) is atoxin found instar 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 bothNMDA andAMPA glutamatergic ionotropic receptors with potent excitatory, convulsant, and neurodegenerative properties.[43]
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 bySouth American tribes onarrows ordarts, though it has matured to specify a specific categorization of poisons which act on theneuromuscular junction to inhibit signaling and thus induce muscle relaxation.[86] The neurotoxin category contains a number of distinct poisons, though all were originally purified from plants originating in South America.[86] The effect with which injected curare poison is usually associated is muscle paralysis and resultant death.[87] Curare notably functions to inhibitnicotinic acetylcholine receptors at theneuromuscular 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 byanesthesiologists to produce muscular relaxation.[88]
Ammonia toxicity is often seen through two routes of administration, either through consumption or through endogenous ailments such asliver failure.[89][90] One notable case in which ammonia toxicity is common is in response tocirrhosis of theliver which results inhepatic encephalopathy, and can result incerebral 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 ofcGMP (Cyclic Guanosine Monophosphate) within the cells which leads toProtein Kinase G-mediated (PKG) cytoskeletal modifications.[46] The resultant effect of this toxicity can be reduced brain energymetabolism and function. Importantly, the toxic effects of ammonia on astrocyte remodeling can be reduced through administration ofL-carnitine.[89] This astrocyte remodeling appears to be mediated through ammonia-inducedmitochondrial permeability transition. This mitochondrial transition is a direct result ofglutamine activity a compound which forms from ammonia in-vivo.[91] Administration ofantioxidants orglutaminase inhibitor can reduce this mitochondrial transition, and potentially also astrocyte remodeling.[91]
Arsenic is a neurotoxin commonly found concentrated in areas exposed toagricultural runoff,mining, andsmelting sites (Martinez-Finley 2011). One of the effects of arsenic ingestion during the development of the nervous system is the inhibition ofneurite growth[92] which can occur both in PNS and the CNS.[93] This neurite growth inhibition can often lead to defects inneural migration, and significant morphological changes of neurons duringdevelopment,[94]) often leading toneural tube defects inneonates.[95] As ametabolite 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 inintracellular calcium ion levels within neurons, which may subsequently reduce mitochondrial transmembrane potential which activatescaspases, triggering cell death.[94] Another known function of arsenite is its destructive nature towards thecytoskeleton through inhibition ofneurofilament transport.[47] 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.[96] Additionally, similar to other neurotoxin treatments, the administration of certain antioxidants has shown some promise in reducing neurotoxicity of ingested arsenic.[94]
Lead is a potent neurotoxin whose toxicity has been recognized for at least thousands of years.[97] Though neurotoxic effects for lead are found in bothadults and youngchildren, the developing brain is particularly susceptible to lead-induced harm, effects which can includeapoptosis and excitotoxicity.[97] An underlying mechanism by which lead is able to cause harm is its ability to be transported bycalcium ATPase pumps across the BBB, allowing for direct contact with the fragile cells within the central nervous system.[98] 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 cellularhomeostasis and induces apoptosis.[48] It is this intracellular calcium increase that activatesprotein kinase C (PKC), which manifests as learning deficits in children as a result of early lead exposure.[48] In addition to inducing apoptosis, lead inhibits interneuron signaling through the disruption of calcium-mediated neurotransmitter release.[99]
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 reducedneurogenesis in thehippocampus,[100][101] widespread brain atrophy,[102] and inducedinflammation in the brain.[103] Of note, chronic ethanol ingestion has additionally been shown to induce reorganization of cellular membrane constituents, leading to alipid bilayer marked by increased membrane concentrations ofcholesterol andsaturated fat.[50] 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 inhibitNMDA receptors in the hippocampus, resulting in reducedlong-term potentiation (LTP) and memory acquisition.[49] NMDA has been shown to play an important role in LTP and consequently memory formation.[104] With chronic ethanol intake, however, the susceptibility of these NMDA receptors to induce LTP increases in themesolimbic dopamine neurons in aninositol 1,4,5-triphosphate (IP3) dependent manner.[105] 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.[106]
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.[107] This work was responsible for creating the classification offetal alcohol syndrome, a disease characterized by commonmorphogenesis aberrations such as defects incraniofacial formation, limb development, andcardiovascular formation. The magnitude of ethanol neurotoxicity infetuses leading to fetal alcohol syndrome has been shown to be dependent on antioxidant levels in the brain such asvitamin E.[108] 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 andcerebellum. 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.[109] 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 ofreactive oxidative species (ROS).[30] This is a plausible mechanism, as there is a reduced presence in the fetal brain of antioxidant enzymes such ascatalase andperoxidase.[110] In support of this mechanism, administration of high levels ofdietary vitamin E results in reduced or eliminated ethanol-induced neurotoxic effects in fetuses.[8]
n-Hexane is a neurotoxin which has been responsible for the poisoning of several workers in Chinese electronics factories in recent years.[111][112][113][51]
MPP+, the toxic metabolite ofMPTP is a selective neurotoxin which interferes withoxidative phosphorylation inmitochondria by inhibitingcomplex I, leading to the depletion ofATP and subsequent cell death. This occurs almost exclusively in dopaminergic neurons of thesubstantia nigra, resulting in the presentation of permanentparkinsonism in exposed subjects 2–3 days after administration.
Unlike most common sources of neurotoxins which are acquired by the body through ingestion, endogenous neurotoxins both originate from and exert their effectsin-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.[114] It is often only when these endogenous compounds become highly concentrated that they lead to dangerous effects.[9]
Thoughnitric oxide (NO) is commonly used by the nervous system in inter-neuron communication and signaling, it can be active in mechanisms leading toischemia 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.[52] Though NO facilitates increased blood flow to potentially ischemic regions of the brain, it is also capable of increasingoxidative stress,[115] inducing DNA damage and apoptosis.[116] Thus an increased presence of NO in an ischemic area of the CNS can produce significantly toxic effects.
Glutamate, like nitric oxide, is an endogenously produced compound used by neurons to perform normally, being present in small concentrations throughout thegray matter of the CNS.[9] One of the most notable uses of endogenous glutamate is its functionality as an excitatory neurotransmitter.[53] 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.[53] Support has been shown for these mechanisms playing significant roles in diseases and complications such asHuntington's disease,epilepsy, andstroke.[9]
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