Benchmark II axl90

Neurotoxin

Neurotoxin (from Ancient Greek: νευρών neuron “sinew” and τοξικόν toxikon “toxin”) is classification given to an extensive category of exogenous chemical neurological insults (Spencer 2000) which can adversely affect function in both developing and mature nervous tissue (Olney 2002), though can also be used to classify endogenous compounds which when abnormally concentrated can also prove neurologically toxic(Spencer 2000). Though neurotoxins may commonly be viewed as neurologically destructive, they have significant applications in studying nervous system (Kiernan 2005). Common examples of neurotoxins include lead (Lidsky 2003), ethanol (Heaton 2000), phencyclidine (PCP), ketamine, glutamate (Choi 1987), nitric oxide (NO) (Zhang 1994), botulinum toxin (Rosales 1996), tatanus toxin (Simpson 1986), and tetrodotoxin (Kiernan 2005). Neurotoxin activity is often characterized by the ability to inhibit neuron control over ion concentrations across the cell membrane (Kiernan 2005), or inter-neuron communication across a synapse (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 retardation (Olney 2002), persistent memory impairments (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 (Heaton 2000), antitoxin (Thyagarajan 2009) and ethanol (Takadera 1990) administration.

Background

Illustration of typical Multipolar neuron.

Exposure to neurotoxins in society is not new as civilizations have been exposed to neurologically destructive compounds for thousands of years. One notable example is possible significant lead exposure during the Roman empire resulting from the development of extensive plumbing networks (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. However, as with any highly complex system, 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 leading to compounding of damages (Dobbs 2009). As such, the nervous system has a number of mechanisms designed to protect it from internal, and external insults. The blood brain barrier (BBB) is one critical example of protection which prevents toxins and other adverse compounds from reaching the brain (Widmaier 2008). As the brain requires nutrient entry and waste removal, it is perfused by blood flow, however blood can carrier a number of ingested toxins which would induce significant neuron death if ever coming into contact with the nervous tissue. Thus, protective cells termed astrocytes surround the capillaries in the skull and absorb nutrients from the blood and subsequently transporting them to the neurons, effectively isolating the brain from a number of potential chemical insults (Widmaier 2008).

Astrocytes surrounding capillaries in the Brain to form the Blood Brain Barrier.

This barrier creates a tight hydrophobic layer around the capillaries in the brain, inhibiting the transport of a 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 plexusus 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 while trapping heavy metals such as lead, the choroid plexuses maintain a strictly regulated environment which contains the brain and spinal cord (Widmaier 2008, Martini 2009).

Choroid Plexus.

By being hydrophobic and small or inhibiting astrocyte function, some compounds including certain neurotoxins are able to penetrate into the brain and induce significant damage. On modern times, scientists and physicians have been presented with the challenge of identifying and treating neurotoxins, which has resulting 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 identification and classification of many environmental neurotoxins, such that there are roughly between 750 and 1000 known potentially neurotoxic compounds (Dobbs 2009). Due to the critical importance of finding neurotoxins in common environments, specific protocols have been developed by the EPA for testing and determining neurotoxic effects of compounds (USEPA 1998). Additionally, in-vitro systems have increased in use as they provide significant improvements over the more common in-vivo systems of the past, such as tractable, uniform environments, and the elimination of contaminating effects of systemic metabolism (Costa 2011). However, in-vitro systems 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 (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 skeletal modifications may occur in response to either (Gartlon 2006). Recently in an effort to address this complication, neurite outgrowths (either axonal or dendritic) in response to applied compounds have been proposed as a more accurate distinction between true neurotoxins and cytotoxins in an in-vitro testing environment. However, due to the significant inaccuracies associated with this process, it has been slow in gaining widespread support (Mundy 2008). Additionally, biochemical mechanisms have become more widely used in neurotoxin testing, such that compounds can be screened for sufficiency to induce cell mechanism interference, such as the inhibition of acetylcholinesterase capacity of organophosphates (includes DDT and sarin gas) (Lotti 2005). Though methods of determining neurotoxicity still require significant development, the identification of deleterious compounds and and toxin exposure symptoms has undergone significant improvement.

Mechanisms of Activity

As neurotoxins are compounds which adversely affect the nervous system, a number of mechanisms through which they function will be 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 (Arnon 2001), 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 (Thyagarajan 2009) and years for lead (Lewendon 2001).

Neurotoxin Classification	Neurotoxin
NMDA Inhibitor	Ethanol
Na Channel Inhibitor	Tetrodotoxin
K Channel Inhibitor	Tetra-ethyl Ammonium
Cl Channel Inhibitor	Chlorotoxin
Ca Channel Inhibitor
Vesiclar Communication Inhibitor	Botulinum Toxin, Tetanus Toxin
Blood Brain Barrier Inhibitor	Aluminum, Mercury

Endogenous Neurotoxin Sources

Introduction clarifying why these are different from exogenous neurotoxins in that they may be quite useful and important to the system.

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 (Garthwaite 1988). 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.

Bacterial Neurotoxin Sources

Botulinum Toxin

Mechanism of Botulinum Toxin neurotoxicity.

Botulinum Toxin (BTX) is group of neurotoxins consisting of seven distinct compounds, referred to as BTX-A,B,C,D,E,F,G which are produced by the bacterium Clostridium Botulinum, and lead to muscular paralysis (Brin 1998). A notably unique feature of BTX is its relatively common therapeutic use in treating dystonia and spasticity disorders (Brin 1998) as well as in inducing muscular atrophy (Rosales 1996) despite being the most poisonous substance known (Thyagarajan 2009). BTX functions peripherally to inhibit acetylcholine (ACh) release at the neuromuscular junction through degradation of the SNARE proteins required for ACh vesicle-membrane fusion (Garcia-Rodriguez 2011). 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 (Arnon 2001). 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 receptor expressed on cholinergic neurons and inhibit the toxic effects of BTX (Thyagarajan 2009).

Tetanus Toxin

Tetanus neurotoxin (TeNT) is a compound that functionally reduces inhibitory transmissions in the nervous system resulting in muscular tetany.

Clostridium Tetani Bacteria.

TeNT is similar to BTX, and is in fact highly similar in structure and origin, both belonging to the same category of clostridial neurotoxins (Simpson 1986). Like BTX, TeNT inhibits inter-neuron communication by means of vesicular neurotransmitter (NT) release (Williamson 1996). One notable difference between the two compounds is that while BTX inhibits 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 (CNS) (Montecucco 1986). This is a result of TeNT migration to through motor neurons 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 (Pirazzini 2011).

Venom Neurotoxin Sources

Chlorotoxin

Chlorotoxin (Cltx) is a the active compound found in scorpion venom, and is primarily toxic because of its ability to inhibit the conductance of chlorine channels (DeBin 1993). Ingestion of lethal volumes Cltx results in paralysis through this ion channel disruption. Similar to botulinum toxin, Cltx has been shown to possess significant therapeutic value. Evidence has been 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 (Deshane 2003, Soroceanu 1998).

Tetrodotoxin

The Puffer Fish; a well known Tetrodoxin producer.

Tetrodotoxin (TTX) is a poison produced by organisms belonging to the Tetraodontoidea order, which includes the puffer fish, ocean sunfish, and porcupine fish (Chowdhury 2007). Within the puffer fish, which is a common delicacy especially in Japan, TTX is found in the liver, gonads, ovaries, intestines, and skin (Ahasan 2004, Kiernan 2005). TTX can be fatal if consumed, and has become common form of poisoning in many countries (How 2003). Common symptoms of TTX consumption include paraesthesia, (often restricted to the mouth and limbs) muscle weakness, nausea, and vomiting (Chowdhury 2007) 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 phase of neuron action potentials (Kiernan 2005).

Inhibited signaling response resulting from neuron exposure to tetrodotoxin.

TTX-resistant (TTX-r) is another form of sodium channel which has limited sensitivity to TTX, and is largely found in small diameter axons such as those found in nociception neurons (Kiernan 2005). When significant levels 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 (Kiernan 2005). 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. However, the use of the acetylcholinesterase inhibitor Neostigmine, or the acetylcholine antagonist Atropine can increase sympathetic nerve activity enough to improve survival after TTX exposure (Chowdhury 2007).

Metallic Neurotoxin Sources

Aluminum

Neurotoxic behavior of aluminum 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 (King 1981). Patients experiencing aluminum toxicity can exhibit symptoms such as impaired learning and reduced motor coordination (Rabe 1982). Additionally, systemic aluminum 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).

Mercury

Mercury is capable of inducing CNS damage by migrating into the brain by crossing the BBB (Aschner 1990). Mercury exists in a number of different compounds, though methylmercury (MeHg) is the only significantly neurotoxic form (Aschner 1990). 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 (BroAokes 1988).

Organically Synthesized Neurotoxin Sources

Ethanol

Chronic ethanol ingestion has been shown to induce reorganization of cellular membrane constituents, favoring a bilayer marked by increased membrane concentrations of cholesterol and saturated fat (Leonard 1986). 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 receptors in the hippocampus resulting in reduced LTP and memory acquisition (Lovinger 1989). However, with chronic ethanol intake, the susceptibility of these NMDA receptors to induce LTP increases in the mesolimbic dopamine neurons increases 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. 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).

Example of individual with Fetal Alcohol Syndrome.

This work was responsible for creating the classification of fetal alcohol system; a disease characterized by common morphogenesis aberrations such as defects in craniofacial formation, limb development, and cardiovascular formation. The magnitude of ethanol neurotoxicity in fetuses leading to fetal alcohol syndrome has been shown to be dependent on antioxidant levels in the brain such as vitamin E (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) (Brocardo 2011) This is a plausable mechanism, as there is a reduced presence in the fetal brain of antioxidant enzymes such as catalase and peroxidase (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 (Heaton 2000).

One example is the mechanism of ethanol neurotoxicity through its inhibition of the NMDA glutamate receptor. NMDA has been shown to play an important role in long-term potentiation (LTP) and consequently memory formation (Davis 1992). However, it has been shown that ethanol directly reduces intracellular Ca2+ accumulation through inhibited NMDA receptor activity, and thus reduced capacity for the occurrence of LTP (Takadera 1990).

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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
• Neurotoxicology at Elsevier Journals
• Neurotoxin Institute at Neurotoxin Institute
• Neurotoxins at Toxipedia