Neurotoxin

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 the Roman Empire resulting from the development of extensive plumbing networks and the habit of boiling vinegared wine in lead pans to sweeten it, the process generating lead acetate, known as "sugar of lead".^[20] 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.^[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.

The blood–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 termed astrocytes 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 tight

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 and physicians 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 the United 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 common in 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 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.^[26]

In an effort to address this complication,

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 venomous organisms often use their neurotoxins to subdue a predator or prey very rapidly, toxins have evolved to become highly specific to their target channels such that the toxin does not readily bind other targets^[29] (see Ion Channel toxins). As such, neurotoxins provide an effective means by which certain elements of the nervous system may be accurately and efficiently targeted. An early example of neurotoxin based targeting used radiolabeled tetrodotoxin to assay sodium channels and obtain precise measurements about their concentration along nerve membranes.^[29] 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.^[29] From this basic understanding, the use of common compounds such as tetrodotoxin, tetraethylammonium, and bungarotoxins have led to a much deeper understanding of the distinct ways in which individual neurons may behave.

Mechanisms of activity

As neurotoxins are compounds which adversely affect the nervous system, a number of mechanisms through which they function are through the inhibition of neuron cellular processes. These inhibited processes can range from membrane depolarization mechanisms to inter-neuron communication. By inhibiting the ability for neurons to perform their expected intracellular functions, or pass a signal to a neighboring cell, neurotoxins can induce systemic nervous system arrest as in the case of botulinum toxin,^[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]

Inhibitors

Sodium channel

Tetrodotoxin

Chlorotoxin (Cltx) is the active compound found in scorpion venom, and is primarily toxic because of its ability to inhibit the conductance of chloride channels.^[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 for gliomas to infiltrate healthy nervous tissue in the brain, significantly reducing the potential invasive harm caused by tumors.^[61][62]

Calcium channel

Conotoxin

asphyxiation.^[13] 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.^[18]

Tetanus toxin

suffocation.^[69]

Blood brain barrier

Aluminium

Neurotoxic behavior of

symptoms such as impaired learning and reduced motor coordination.^[71] 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.^[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

glutamate (Glu) transport, potentially leading to excitotoxic effects.^[74]

Receptor agonists and antagonists

Anatoxin-a

External videos
Very Fast Death Factor University of Nottingham

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.^[41][42] 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.^[75]

Toxic effects from anatoxin-a progress very rapidly because it acts directly on the nerve cells (

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.^[76][77]

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.^[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

κ-bungarotoxin is specific for nAChRs found in neurons.^[85]

Caramboxin

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 and AMPA glutamatergic ionotropic receptors with potent excitatory, convulsant, and neurodegenerative properties.^[43]

Curare

The term "

anesthesiologists to produce muscular relaxation.^[88]

Cytoskeleton interference

Ammonia

mitochondrial permeability transition. This mitochondrial transition is a direct result of glutamine activity a compound which forms from ammonia in-vivo.^[91] Administration of antioxidants or glutaminase inhibitor can reduce this mitochondrial transition, and potentially also astrocyte remodeling.^[91]

Arsenic

intracellular calcium ion levels within neurons, which may subsequently reduce mitochondrial transmembrane potential which activates caspases, triggering cell death.^[94] Another known function of arsenite is its destructive nature towards the cytoskeleton through inhibition of neurofilament 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]

Calcium-mediated cytotoxicity

Lead

calcium 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 cellular homeostasis and induces apoptosis.^[48] 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.^[48] In addition to inducing apoptosis, lead inhibits interneuron signaling through the disruption of calcium-mediated neurotransmitter release.^[99]

Neurotoxins with multiple effects

Ethanol

Fetal Alcohol Syndrome

(FAS).

As a neurotoxin,

inositol 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.

vitamin 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 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.^[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 of reactive oxidative species (ROS).^[30] This is a plausible mechanism, as there is a reduced presence in the fetal brain of antioxidant enzymes such as catalase and peroxidase.^[110] In support of this mechanism, administration of high levels of dietary vitamin E results in reduced or eliminated ethanol-induced neurotoxic effects in fetuses.^[8]

n-Hexane

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]}

Receptor-selective neurotoxins

MPP⁺

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.^[114] It is often only when these endogenous compounds become highly concentrated that they lead to dangerous effects.^[9]

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.^[52] Though NO facilitates increased blood flow to potentially ischemic regions of the brain, it is also capable of increasing oxidative 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

gray 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 as Huntington's disease, epilepsy, and stroke.^[9]

See also

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

Notes

1. ^ Sivonen, K (1999). "Toxins produced by cyanobacteria". Vesitalous. 5: 11–18.
2. ^ Scottish Government Blue-Green Algae (Cyanobacteria) in Inland Waters: Assessment and Control of Risks to Public Health Retrieved 15 December 2011.
3. ^ Dorland's Medical Dictionary for Health Consumers
4. ^ ^{a b} Spencer 2000
5. ^ ^{a b} Olney 2002
6. ^ ^{a b c d e f g h} Kiernan 2005
7. ^ Lidsky 2003
8. ^
   PMID 10798588
   .
9. ^ ^{a b c d} Choi 1987
10. ^ Zhang 1994
11. ^
    S2CID 20849034
    .
12. ^ ^{a b} Simpson 1986
13. ^ ^{a b c} Arnon 2001
14. ^ Dikranian 2001
15. ^ Deng 2003
16. ^ Jevtovic-Todorovic 2003
17. ^ Nadler 1978
18. ^ ^{a b c d} Thyagarajan 2009
19. ^ Neurotoxins: Definition, Epidemiology, Etiology
20. ^ Hodge 2002
21. ^ ^{a b} Dobbs 2009
22. ^ ^{a b c} 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.
23. ^ ^{a b} Martini 2009
24. ^ ^{a b} Costa 2011
25. ^ Harry 1998
26. ^ Gartlon 2006
27. PMID 18403021
    .
28. ^ Lotti 2005
29. ^ ^{a b c} Adams 2003
30. ^ ^{a b} Brocardo 2011
31. ^ Lewendon 2001
32. ^ ^{a b} Haghdoost-Yazdi 2011
33. ^ ^{a b} DeBin 1993
34. ^ McClesky 1987
35. ^ ^{a b} Garcia-Rodriguez 2011
36. ^ ^{a b} Williamson 1996
37. ^ ^{a b} Banks 1988
38. ^ ^{a b c} Aschner 1990
39. ^ ^{a b c} Dutertre 2006
40. ^ Koller 1988
41. ^ ^{a b} Carmichael 1978
42. ^ ^{a b} Carmichael 1975
43. ^
    PMID 24281890
    .
44. ^ Rutgrere 2012
45. ^ Roller 1994
46. ^ ^{a b} Konopacka 2009
47. ^ ^{a b} DeFuria 2006
48. ^ ^{a b c} Bressler 1999
49. ^
    PMID 2467382
    .
50. ^
    PMID 2434114
    .
51. ^ ^{a b} Occupational Safety and Health Guideline for n-Hexane Archived 2011-12-18 at the Wayback Machine, OSHA.gov
52. ^ ^{a b} Garthwaite 1988
53. ^ ^{a b c} Choi 1990
54. S2CID 9060404
    .
55. ^
    PMID 17728964
    .
56. ^ Ahasan 2004
57. ^ Lau 1995
58. ^ ^{a b c} Standfield 1983
59. ^ Roed 1989
60. ^ Haghdoost-Yasdi 2011
61. ^ Deshane 2003
62. ^ Soroceanu 1998
63. ^ ^{a b} Jacob 2010
64. ^ Olivera 1987
65. ^ Cruz 1986
66. ^ McCleskey 1987
67. ^ ^{a b} Brin, Mitchell F (1997) "Botulinum Toxin: Chemistry, Pharmacology, Toxicity, and Immunology." Muscle & Nerve, 20 (S6): 146–68.
68. ^ Montecucco 1986
69. ^ ^{a b} Pirazzini 2011
70. ^ King 1981
71. ^ Rabe 1982
72. ^ Walton 2006
73. ^ Chan 2011
74. ^ Brookes 1988
75. ^ Yang 2007
76. ^ Wood 2007
77. ^ National Center for Environmental Assessment
78. ^ Devlin 1977
79. ^ Moore 1977
80. ^ Metcalf 2009
81. ^ Stewart 2008
82. ^ Dixit 2005
83. ^ Tsetlin 2003
84. ^ ^{a b} Liu 2008
85. ^ Hue 2007
86. ^ ^{a b} Bisset 1992
87. ^ Schlesinger 1946
88. S2CID 71400545
    .
89. ^ ^{a b} Matsuoka 1991
90. ^ Buzanska (2000)
91. ^ ^{a b} Norenberg 2004
92. ^ Liu 2009^{[full citation needed]}
93. ^ Vahidnia 2007
94. ^ ^{a b c} Rocha 2011
95. ^ Brender 2005
96. ^ DeFuria 2007
97. ^ ^{a b} Lidskey 2003
98. ^ Bradbury 1993
99. ^ Lasley 1999
100. ^ Taffe 2010
101. ^ Morris 2009
102. ^ Bleich 2003
103. ^ Blanco 2005
104. ^ Davis 1992
105. ^ Bernier 2011
106. ^ Takadera 1990
107. ^ Jones 1973
108. ^ Mitchell 1999
109. ^ Gil-Mohapel 2010
110. ^ Bergamini 2004
111. ^ Workers poisoned while making iPhones ABC News, October 25, 2010
112. ^ Dirty Secrets Archived 2017-05-25 at the Wayback Machine ABC Foreign Correspondent, 2010-Oct-26
113. ^ Mr Daisey and the Apple Factory, This American Life, January 6, 2012
114. ^ Iadecola 1998
115. ^ Beckman 1990
116. ^ Bonfoco 1995

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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

Look up neurotoxin in Wiktionary, the free dictionary.

Wikimedia Commons has media related to Neurotoxins.

• 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
• [1] Neurotoxins] at Toxipedia