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Neurotoxin

Neurotoxin (from Ancient Greek: νευρών neuron “sinew” and τοξικόν toxikon “toxin”) is classification given to an extensive category of endogenous and exogenous neurological insults (Spencer 2000) which can adversely affect function in both developing and mature nervous tissue (Olney 2002). 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.

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

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

Clostridium Tetani Bacteria.

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 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).

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). 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).

Notes (Not to be included in final article)

Botulinum Toxin Mechanism.png Mechanism of Botulinum toxin neurotoxicity. In properly functioning synapse, synaptotagmins will be able to function properly, facilitating vesicle fusion with neuron membrane at synapse. In presence of botulinum toxin, synaptotagmins are degraded, inhibiting the ability for vesicles to fuse to the neuron membrane and release ACh into the synapse. As such, inter-neuron communication will be significantly impaired.

Clostridium Tetani.jpg Source: Department of Microbiology, University of Athens, Greece Date: 1976 Creator: Χαράλαμπος Γκούβας License: Public Domain

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β-Amyloid peptide (βAP) (Hensely 1994)

Ions can play a role in regulating neurotoxicity of compounds, as seen during chemically induced hypoxia where intracellular Ca accumulation leads to neuron necrosis, but inhibition of Ca accumulation protects from injury (Choi 1988).

Neurotoxins are often most biologically influential during synaptogenesis, as this period is characterized by rapid nervous system growth and development as well as a hypersensitivity neurons to external disturbances (Olney 2002).

Disturbances from compounds of this nature induce neuron degeneration through altered glutamate and GABA neurotransmitter release patterns including altered NMDA and GAMA receptor activity, resulting in excitotoxicity or apoptosis, two mechanisms by which neurotoxins may manifest their effects.

Excitotoxicity is necrosis in response to hyperstimulation, and apoptosis is a physiologically programmed suicidal process by which redundant or unsuccessful neurons are eliminated (Dikranian 2001).

NMDA antagonists and GABAmimetics are a category of compounds used to induce general anesthesia, and have been shown to induced general apoptotic neurodegeneration during synaptogenesis, resulting in persistent memory and learning impairments (Jevtovic-Todorovic 2003).

Neurotoxins can also function through disruption of glial cell function such that insults to astrocytes, oligodendrocytes, and Schwann cells will involve subsequent induced neuron apoptosis (Deng 2003).

It is also possible that compounds essential to neuron function can act as neurotoxins, as glutamate, an important NT can function both in excitatory signaling, and as a toxin when in high concentrations (Choi 1987). Effects of widespread glutamate neurotoxicity can lead to complications such as Hunington’s disease (Coyle 1976), epilepsy, and dementia (Nadler 1978).

The number of known neurotoxins is extensive, with recent evidence being shown for 372 known substances possessing evident neurotoxicity (Spencer 2000).

NO can act as neurotoxin (Dawson 1991).

Neuronal injury can be ameliorated by the intake of antioxidants (Lafon-Cazal 1993), an example being ethanol leads to loss of Purkinje cells in the Cerebellum in fetuses, which can be rescued by the intake of substantial quantities of vitamin E (Heaton 2000).

β-Amyloid peptide (βAP) which is an important factor of Alzheimer’s disease can potentiate glutamate excitotoxicity (Hensley 1994).

Often neurotoxins function through the inhibition of ion channels, such as tetrodotoxin from the puffer fish which inhibits functionality of Na channels leading to (Kiernan 2005).

Ethanol can inhibit NMDA mediated Ca influx leading to reduced excitotoxicity (Takadera 1990).

Ca accumulation occurs in response to a number of insults, including epilepsy, physical trauma, and ischemia, suggesting its importance in providing a controlling mechanism for acute neuronal degeneration and delayed neurotoxicity (Tymianski 1993).

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