Neurotoxins are that are destructive to nervous tissue (causing neurotoxicity).[Dorland's Medical Dictionary for Health Consumers] Neurotoxins are an extensive class of exogenous chemical neurological insults[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 compounds, which, when abnormally contacted, can prove neurologically toxic.[Lidsky 2003] ethanol (drinking alcohol),[Choi 1987] nitric oxide,[Zhang 1994] botulinum toxin (e.g. Botox),[Simpson 1986] and tetrodotoxin.
Neurotoxins inhibit neuron control over ion concentrations across the cell membrane,[Arnon 2001] Local pathology of neurotoxin exposure often includes neuron excitotoxicity or apoptosis[Dikranian 2001] but can also include glial cell damage.[Deng 2003] Macroscopic manifestations of neurotoxin exposure can include widespread central nervous system damage such as intellectual disability,[Jevtovic-Todorovic 2003] epilepsy, and dementia.[Nadler 1978] Additionally, neurotoxin-mediated peripheral nervous system damage such as neuropathy or myopathy is common. Support has been shown for a number of treatments aimed at attenuating neurotoxin-mediated injury, such as antioxidant[Thyagarajan 2009] administration.
Background
Exposure to neurotoxins in society is not new,
[ Neurotoxins: Definition, Epidemiology, Etiology] as civilizations have been exposed to neurologically destructive compounds for thousands of years. One notable example is the possible significant lead exposure during the
Roman Empire resulting from the development of extensive
plumbing and the habit of boiling vinegared wine in lead pans to sweeten it. The process generates
lead acetate, known as "sugar of lead".
[Hodge 2002] In part, neurotoxins have been part of
human history because of the fragile and susceptible nature of the nervous system, making it highly prone to disruption.
The nervous tissue found in the brain, spinal cord, and periphery comprises an extraordinarily complex biological system that largely defines many of the unique traits of individuals. As with any highly complex system, however, even small perturbations to its environment can lead to significant functional disruptions. Properties leading to the susceptibility of nervous tissue include a high surface area of neurons, a high lipid content which retains lipophilic toxins, high blood flow to the brain inducing increased effective toxin exposure, and the persistence of neurons through an individual's lifetime, leading to compounding of damages.[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 (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 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 layer around the capillary in the brain, inhibiting the transport of large or hydrophilic compounds. In addition to the BBB, the choroid plexus provides a layer of protection against toxin absorption in the brain. The choroid plexuses are vascularized layers of tissue found in the third, fourth, and lateral ventricles of the brain, which through the function of their ependymal cells, are responsible for the synthesis of cerebrospinal fluid (CSF).[Martini 2009] Importantly, through selective passage of ions and nutrients and trapping heavy metals such as lead, the choroid plexuses maintain a strictly regulated environment which contains the brain and spinal cord.
By being hydrophobic and small, or inhibiting astrocyte function, some compounds including certain neurotoxins are able to penetrate into the brain and induce significant damage. In modern times, and 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.[Harry 1998] To even further complicate the process of determining neurotoxins when testing in-vitro, neurotoxicity and cytotoxicity may be difficult to distinguish as exposing neurons directly to compounds may not be possible in-vivo, as it is in-vitro. Additionally, the response of cells to chemicals may not accurately convey a distinction between neurotoxins and cytotoxins, as symptoms like oxidative stress or human skeleton modifications may occur in response to either.[Gartlon 2006]
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 in an in-vitro testing environment. Due to the significant inaccuracies associated with this process, however, it has been slow in gaining widespread support.[Lotti 2005] Though methods of determining neurotoxicity still require significant development, the identification of deleterious compounds and toxin exposure symptoms has undergone significant improvement.
Applications in neuroscience
Though diverse in chemical properties and functions, neurotoxins share the common property that they act by some mechanism leading to either the disruption or destruction of necessary components within the
nervous system. Neurotoxins, however, by their very design can be very useful in the field of
neuroscience. As the nervous system in most organisms is both highly complex and necessary for survival, it has naturally become a target for attack by both predators and prey. As
venom 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
[Adams 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
and obtain precise measurements about their concentration along nerve
cell membrane.
Likewise through isolation of certain channel activities, neurotoxins have provided the ability to improve the original Hodgkin-Huxley model of the neuron in which it was theorized that single generic sodium and potassium channels could account for most nervous tissue function.
From this basic understanding, the use of common compounds such as tetrodotoxin, tetraethylammonium, and
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
synapse. By inhibiting the ability for neurons to perform their expected intracellular functions, or pass a signal to a neighboring cell, neurotoxins can induce systemic nervous system arrest as in the case of
botulinum toxin,
or even nervous tissue death.
[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.
[Lewendon 2001]
|
|
| Na channel inhibitors | Tetrodotoxin[Kiernan 2005] |
| K channel inhibitors | Tetraethylammonium[Haghdoost-Yazdi 2011] |
| Cl channel inhibitors | Chlorotoxin,[DeBin 1993] |
| Ca channel inhibitors | Conotoxin[McClesky 1987] |
| Inhibitors of synaptic vesicle release | Botulinum toxin,[Garcia-Rodriguez 2011]
Tetanus[Williamson 1996] |
| Blood brain barrier inhibitors | Aluminium,
Mercury[Aschner 1990] |
| Receptor inhibitors/antagonists | Bungarotoxin,[Dutertre 2006]
Curare[Koller 1988] |
| Receptor agonists | Anatoxin-a,
Caramboxin,
25I-NBOMe,[Rutgrere 2012]
JWH-018,[Roller 1994]
5-MEO-DiPT |
| Cytoskeleton interference | Ammonia,[Konopacka 2009]
Arsenic[DeFuria 2006] |
| Ca-mediated cytotoxicity | Lead[Bressler 1999] |
| Protein misfolding | Tau protein |
| Multiple effects | Ethanol,
N-Hexane,
Methanol |
| Receptor-selective neurotoxins | MPP+ |
| Endogenous neurotoxin sources | Nitric oxide,[Garthwaite 1988]
Glutamate,[Choi 1990]
Dopamine |
Inhibitors
Sodium channel
Tetrodotoxin
Tetrodotoxin (TTX) is a poison produced by organisms belonging to the Tetraodontiformes order, which includes the
puffer fish,
Molidae, and
porcupine fish.
Within the puffer fish, TTX is found in the
liver,
gonads,
intestines, and
skin.
[Ahasan 2004] TTX can be fatal if consumed, and has become a common form of poisoning in many countries. Common symptoms of TTX consumption include
paraesthesia (often restricted to the
mouth and limbs), muscle weakness,
nausea, and
vomiting and often manifest within 30 minutes of
ingestion.
[Lau 1995] 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 of neuron
.
TTX-resistant (TTX-r) is another form of sodium channel which has limited sensitivity to TTX, and is largely found in
axon such as those found in
nociceptor.
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
action potential is a reduced excitability of
chemical synapse, and subsequent loss of motor and sensory function which can result in paralysis and death. Though assisted ventilation may increase the chance of survival after TTX exposure, there is currently no antitoxin. The use of the acetylcholinesterase inhibitor
Neostigmine or the muscarinic acetylcholine antagonist
atropine (which will inhibit parasympathetic activity), however, can increase sympathetic nerve activity enough to improve the chance of survival after TTX exposure.
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 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 seen in an
action potential and some population of calcium-dependent potassium channels.
It is this capability to inhibit potassium flux in neurons that has made TEA one of the most important tools in neuroscience. It has been hypothesized that the ability for TEA to inhibit potassium channels is derived from its similar space-filling structure to potassium ions.
What makes TEA very useful for
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.
[Roed 1989] 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.
[Haghdoost-Yasdi 2011]
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
.
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
to infiltrate healthy nervous tissue in the brain, significantly reducing the potential invasive harm caused by tumors.
[Deshane 2003][Soroceanu 1998]
Calcium channel
Conotoxin
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][Olivera 1987] In many cases, the toxins released by the different types of
Coninae 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) is highly specific for Ca channels and has shown usefulness in isolating them from a system.
[Cruz 1986] 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.
[McCleskey 1987]
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-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
) can bind the TRPV1 receptor expressed on
cholinergic and inhibit the toxic effects of BTX.
Tetanus toxin
Tetanus (TeNT) is a compound that functionally reduces inhibitory transmissions in the nervous system resulting in muscular tetany. TeNT is similar to BTX, and is in fact highly similar in structure and origin; both belonging to the same category of clostridial neurotoxins.
Like BTX, TeNT inhibits inter-neuron communication by means of vesicular neurotransmitter (NT) release.
One notable difference between the two compounds is that while BTX inhibits
muscle, TeNT induces them. Though both toxins inhibit vesicle release at neuron synapses, the reason for this different manifestation is that BTX functions mainly in the peripheral nervous system (PNS) while TeNT is largely active in the central nervous system (CNS).
[Montecucco 1986] This is a result of TeNT migration through
to the 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 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 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
incapable of removing excess ions from the blood, such as those experiencing
renal failure.
[King 1981] Patients experiencing aluminium toxicity can exhibit
such as impaired learning and reduced motor coordination.
[Rabe 1982] 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.
[Walton 2006] Despite its known toxicity in its ionic form, studies are divided on the potential toxicity of using aluminium in packaging and cooking appliances.
Mercury
Mercury is capable of inducing CNS damage by migrating into the brain by crossing the BBB.
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.
[Chan 2011] It is known that the mercuric ion inhibits
amino acid (AA) and
glutamate (Glu) transport, potentially leading to excitotoxic effects.
[Brookes 1988]
Receptor agonists and antagonists
Anatoxin-a
Investigations into
Anatoxin-a, also known as "Very Fast Death Factor", began in 1961 following the deaths of cows that drank from a lake containing an
algal bloom in Saskatchewan, Canada.
[Carmichael 1978][Carmichael 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.
[Yang 2007]
Toxic effects from anatoxin- a progress very rapidly because it acts directly on the nerve cells (). The progressive symptoms of anatoxin- a exposure are loss of coordination, Fasciculation, convulsions and rapid death by respiratory paralysis. The nerve tissues which communicate with muscles contain a receptor called the nicotinic acetylcholine receptor. Stimulation of these receptors causes a muscular contraction. The anatoxin- a molecule is shaped so it fits this receptor, and in this way it mimics the natural neurotransmitter normally used by the receptor, acetylcholine. Once it has triggered a contraction, anatoxin- a does not allow the neurons to return to their resting state, because it is not degraded by cholinesterase which normally performs this function. As a result, the muscle cells contract permanently, the communication between the brain and the muscles is disrupted and breathing stops.[Wood 2007][National Center for Environmental Assessment]
When it was first discovered, the toxin was called the Very Fast Death Factor (VFDF) because when it was injected into the body cavity of mice it induced tremors, paralysis and death within a few minutes. In 1977, the structure of VFDF was determined as a secondary, bicyclic amine alkaloid, and it was renamed anatoxin- a.[Devlin 1977][Moore 1977] 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
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.
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 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.
[Hue 2007]
Caramboxin
Caramboxin (CBX) is a
toxin found in
star fruit (
Averrhoa carambola). Individuals with some types of kidney disease are susceptible to adverse neurological effects including intoxication, seizures and even death after eating star fruit or drinking juice made of this fruit. Caramboxin is a new nonpeptide amino acid toxin that stimulate the glutamate receptors in neurons. Caramboxin is an agonist of both
NMDA receptor and
AMPA receptor glutamatergic ionotropic receptors with potent excitatory, convulsant, and neurodegenerative properties.
Curare
The term "
curare" is ambiguous because it has been used to describe a number of poisons which at the time of naming were understood differently from present day understandings. In the past the characterization has meant poisons used by South American tribes on
or darts, though it has matured to specify a specific categorization of poisons which act on the neuromuscular junction to inhibit signaling and thus induce muscle relaxation.
[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][Buzanska (2000)] One notable case in which ammonia toxicity is common is in response to
cirrhosis of the
liver which results in hepatic encephalopathy, and can result in
cerebral edema (Haussinger 2006). This cerebral edema can be the result of nervous cell remodeling. As a consequence of increased concentrations, ammonia activity in-vivo has been shown to induce swelling of astrocytes in the brain through increased production of cGMP (Cyclic Guanosine Monophosphate) within the cells which leads to Protein Kinase G-mediated (PKG) cytoskeletal modifications.
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.
This astrocyte remodeling appears to be mediated through ammonia-induced
permeability transition. This mitochondrial transition is a direct result of
glutamine activity a compound which forms from ammonia in-vivo.
[Norenberg 2004] Administration of
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
[Liu 2009] which can occur both in PNS and the CNS.
[Vahidnia 2007] This neurite growth inhibition can often lead to defects in neural migration, and significant morphological changes of neurons during development,
[Rocha 2011]) often leading to
neural tube defects in
infant.
[Brender 2005] 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
, 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.
[DeFuria 2007] 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
and young
, the developing brain is particularly susceptible to lead-induced harm, effects which can include
apoptosis and excitotoxicity.
An underlying mechanism by which lead is able to cause harm is its ability to be transported by
atpase across the BBB, allowing for direct contact with the fragile cells within the central nervous system.
[Bradbury 1993] 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.
[Lasley 1999]
Neurotoxins with multiple effects
Ethanol
As a neurotoxin,
ethanol has been shown to induce nervous system damage and affect the body in a variety of ways. Among the known effects of ethanol exposure are both transient and lasting consequences. Some of the lasting effects include long-term reduced
neurogenesis in the
hippocampus,
[Taffe 2010][Morris 2009] widespread brain atrophy,
[Bleich 2003] and induced
inflammation in the brain.
[Blanco 2005] 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 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.
[Davis 1992] With chronic ethanol intake, however, the susceptibility of these NMDA receptors to induce LTP increases in the mesolimbic dopamine neurons in an inositol 1,4,5-triphosphate (IP3) dependent manner.
[Bernier 2011] 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.[Jones 1973] This work was responsible for creating the classification of fetal alcohol syndrome, a disease characterized by common morphogenesis aberrations such as defects in craniofacial formation, limb development, and cardiovascular formation. The magnitude of ethanol neurotoxicity in leading to fetal alcohol syndrome has been shown to be dependent on antioxidant levels in the brain such as vitamin e.[Mitchell 1999] 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.[Gil-Mohapel 2010] It is known that ethanol exposure results in reduced antioxidant levels, mitochondrial dysfunction (Chu 2007), and subsequent neuronal death, seemingly as a result of increased generation of reactive oxidative species (ROS).[Bergamini 2004] In support of this mechanism, administration of high levels of dietary vitamin E results in reduced or eliminated ethanol-induced neurotoxic effects in fetuses.
n-Hexane
n-
Hexane is a neurotoxin which has been responsible for the poisoning of several workers in Chinese electronics factories in recent years.
[ Workers poisoned while making iPhones ABC News, October 25, 2010][ Dirty Secrets ABC Foreign Correspondent, 2010-Oct-26][ Mr Daisey and the Apple Factory, This American Life, January 6, 2012][ Occupational Safety and Health Guideline for n-Hexane , OSHA.gov]
Receptor-selective neurotoxins
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 ATP and subsequent cell death. This occurs almost exclusively in dopaminergic neurons of the
substantia nigra, resulting in the presentation of permanent
parkinsonism in exposed subjects 2–3 days after administration.
Endogenous neurotoxin sources
Unlike most common sources of neurotoxins which are acquired by the body through ingestion, endogenous neurotoxins both originate from and exert their effects
in vivo. Additionally, though most venoms and exogenous neurotoxins will rarely possess useful in-vivo capabilities, endogenous neurotoxins are commonly used by the body in useful and healthy ways, such as nitric oxide which is used in cell communication.
[Iadecola 1998] It is often only when these endogenous compounds become highly concentrated that they lead to dangerous effects.
Nitric oxide
Though
nitric oxide (NO) is commonly used by the nervous system in inter-neuron communication and signaling, it can be active in mechanisms leading to
ischemia in the cerebrum (Iadecola 1998). The neurotoxicity of NO 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,
[Beckman 1990] 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, and
stroke.
See also
Notes
-
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.
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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.
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