Neurotoxin

A neurotoxin is a toxin that acts specifically on nerve cells^[1] (neurons), usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue.^[2] Bungarotoxin, which is considered a neurotoxin,^[3] has its effect at the motor end plate.

Neurotoxin sources

Exogenous

Toxins ingested from the environment are described as exogenous and include gases (such as carbon monoxide), metals (such as mercury^[4]), liquids (ethanol), and numerous solids. Many neurotoxins are found in plant and animal matter found in nature; for example the neurotoxin aesculin is found in the horse chestnut (Aesculus hippocastanum),^[5] and the California buckeye tree.^[6] When exogenous toxins are ingested, the effect on neurons is largely dependent on dosage.

Endogenous

Neurotoxicity also occurs from substances produced within the body, known as endogenous neurotoxins.^[7] An example of an endogenous neurotoxin is the primary neurotransmitter glutamate, which, when levels reach too high, can result in excitotoxicity and cause neuronal death by apoptosis.

Classification and examples

Venoms

Many of the venoms and other toxins that organisms use in defense against predators are neurotoxins. A common effect is paralysis, which sets in very rapidly. The venom of bees, scorpions, pufferfish, spiders, and snakes can contain many different toxins.

Channel inhibitors

Many neurotoxins act by affecting voltage-dependent ion channels:

Agent	Channel
tetrodotoxin and batrachotoxin	sodium channels
maurotoxin, agitoxin, charybdotoxin, margatoxin, slotoxin, scyllatoxin and hefutoxin	potassium channels
calciseptine, taicatoxin, calcicludine, and PhTx3	calcium channels

A potent neurotoxin such as batrachotoxin affects the nervous system by causing depolarization of nerve and muscle fibers due to increased sodium ion permeability of the excitable cell membrane.

A very potent neurotoxin is tetrodotoxin. This chemical acts to block sodium channels in neurons, preventing action potentials. This leads to paralysis and eventually death.

Saxitoxin is also a very potent natural neurotoxin, produced by some strains of marine dinoflagellates, cyanobacteria and puffer fish.^[8][9][10] Saxitoxins bioaccumulate in shellfish and certain finfish. Ingestion of saxitoxin, usually through shellfish contaminated by toxic algal blooms, can result in paralytic shellfish poisoning.^[11] Together with tetrodoxin, saxitoxin has been used in molecular biology to establish the function of the sodium channel. It acts on the voltage-gated sodium channels of nerve cells, preventing normal cellular function and leading to paralysis. The blocking of neuronal sodium channels which occurs in paralytic shellfish poisoning produces a flaccid paralysis that leaves its victim calm and conscious through the progression of symptoms. Death often occurs from respiratory failure.^[12]

Bungarotoxin is also a very potent neurotoxin. It binds irreversibly and competitively to the acetylcholine receptor found at the end plate of the neuromuscular junction, causing paralysis, and depending on the dose, can cause respiratory failure and death in the victim

Another very potent neurotoxin is taipoxin. The toxin causes a gradual reduction to complete stop of evoked and spontaneous release of acetylcholine from motor nerve terminals. If the dose is high enough, the victim can die from asphyxia caused by paralysis of the respiratory muscles.

Botulinum neurotoxins are the most potent natural toxins known(only tested on laboratory mice). They are produced by various toxigenic strains of Clostridium botulinum and act as metalloproteinases that enter peripheral cholinergic nerve terminals and cleave proteins that are crucial components of the neuroexocytosis apparatus, causing a persistent but reversible inhibition of neurotransmitter release resulting in flaccid muscle paralysis.^[13]

Nerve agents

A number of artificial neurotoxins, known as nerve agents, have been developed for use as chemical weapons.

Neurotoxic drugs

Examples of neurotoxic drugs include, but are not limited to:

• Certain psychostimulants, particularly methamphetamine and to a lesser degree dextroamphetamine and amphetamine, when used at high doses have been shown to cause dopaminergic and serotonergic neurotoxicity via oxidative stress. The neurotoxicity of stimulants such as cocaine and methylphenidate is debatable.
• Empathogen-entactogens such as MDMA and MDA (except MDAI) have been found to cause neurotoxicity to serotonergic nerve terminals, though this claim has been readily disputed.
• L-DOPA induces damage to striatal dopamine neurons, particularly after chronic usage. Also shown to potentiate neurotoxicity of amphetamines and other dopamine releasing agents
• NMDA receptor antagonists like ketamine, PCP, DXM, and dizocilpine (MK-801) have been shown to produce Olney's lesions in rodents, though this has never been observed in humans.
• GHB receptor agonists like GHB, GBL, and 1,4-BD, which damage the cerebral/prefrontal cortex and hippocampus via oxidative stress.^{[14][15][16][17][18][19]}
• NMDA receptor agonists like ibotenic acid (which is found in Amanita muscaria mushrooms) and GABA receptor antagonists like picrotoxin, and bicuculline are neurotoxic via excitotoxicity.^[20]
• Several antipsychotics have been linked to brain gray/white matter loss.^[21]
• Others such as 5,7-DHT, 6-OHDA, MPP+, MPTP, PBA, PCA, and PIA.

See also

• Neurotoxicity
• Olney's Lesions
• Toxin
• Microbial toxins
• Sea anemone neurotoxin
• Snake toxins
• BmKAEP

References

1. ^ "neurotoxin - Definitions from Dictionary.com". dictionary.reference.com. http://dictionary.reference.com/browse/neurotoxin. Retrieved 2008-04-22. 
2. ^ "Dorlands Medical Dictionary:neurotoxin". http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/six/000072135.htm. 
3. ^ Kuch U, Molles BE, Omori-Satoh T, Chanhome L, Samejima Y, Mebs D (September 2003). "Identification of alpha-bungarotoxin (A31) as the major postsynaptic neurotoxin, and complete nucleotide identity of a genomic DNA of Bungarus candidus from Java with exons of the Bungarus multicinctus alpha-bungarotoxin (A31) gene". Toxicon 42 (4): 381–90. doi:10.1016/S0041-0101(03)00168-5. PMID 14505938. http://linkinghub.elsevier.com/retrieve/pii/S0041010103001685. 
4. ^ "United States Environmental Protection Agency: Mercury". http://www.epa.gov/mercury/health.htm. Retrieved 2008-10-15. 
5. ^ Plant poisons: Aesculin
6. ^ C.Michael Hogan (2008) Aesculus californica, Globaltwitcher.com, ed. N. Stromberg
7. ^ Moser, Andreas (1998). Pharmacology of endogenous neurotoxins: a handbook. Boston: Birkhäuser. ISBN 0-8176-3993-4. http://books.google.com/?id=SOferqCZkUMC&printsec=frontcover&dq=endogenous+neurotoxins. 
8. ^ Clark RF, Williams SR, Nordt SP, Manoguerra AS (1999). "A review of selected seafood poisonings". Undersea Hyperb Med 26 (3): 175–84. PMID 10485519. http://archive.rubicon-foundation.org/2314. Retrieved 2008-08-12. 
9. ^ Nakamuraa M, Oshimaa Y and Yasumoto T (1984) "Occurrence of saxitoxin in puffer fish" Toxicon, 22(3): 381-385. doi:10.1016/0041-0101(84)90082-5
10. ^ Landsberg JH, 2002. The effects of harmful algal blooms on aquatic organisms. Reviews in Fisheries Science, 10(2): 113–390.
11. ^ Sinonen K and Jones G (1999) "Cyanobacterial Toxins" In Toxic Cyanobacteria in Water. Chorus I and Bartram J (eds): 41-111. WHO, Geneva.
12. ^ Kao CY and Levinson SR (1986) Tetrodotoxin, saxitoxin, and the molecular biology of the sodium channel. New York Academy of Sciences. ISBN 0897663543.
13. ^ Kukreja R and Singh BR (2009). "Botulinum Neurotoxins: Structure and Mechanism of Action". Microbial Toxins: Current Research and Future Trends. Caister Academic Press. ISBN 978-1-904455-44-8. 
14. ^ Sircar R, Basak A (December 2004). "Adolescent gamma-hydroxybutyric acid exposure decreases cortical N-methyl-D-aspartate receptor and impairs spatial learning". Pharmacology, Biochemistry, and Behavior 79 (4): 701–8. doi:10.1016/j.pbb.2004.09.022. PMID 15582677. http://linkinghub.elsevier.com/retrieve/pii/S0091-3057(04)00320-X. 
15. ^ García FB, Pedraza C, Arias JL, Navarro JF (August 2006). "[Effects of subchronic administration of gammahydroxybutyrate (GHB) on spatial working memory in rats]" (in Spanish; Castilian). Psicothema 18 (3): 519–24. PMID 17296081. 
16. ^ Sgaravatti AM, Sgarbi MB, Testa CG, et al. (February 2007). "Gamma-hydroxybutyric acid induces oxidative stress in cerebral cortex of young rats". Neurochemistry International 50 (3): 564–70. doi:10.1016/j.neuint.2006.11.007. PMID 17197055. http://linkinghub.elsevier.com/retrieve/pii/S0197-0186(06)00335-4. 
17. ^ Sircar R, Basak A, Sircar D (October 2008). "Gamma-hydroxybutyric acid-induced cognitive deficits in the female adolescent rat". Annals of the New York Academy of Sciences 1139: 386–9. doi:10.1196/annals.1432.044. PMID 18991885. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2008&volume=1139&spage=386. 
18. ^ Pedraza C, García FB, Navarro JF (October 2009). "Neurotoxic effects induced by gammahydroxybutyric acid (GHB) in male rats". The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 12 (9): 1165–77. doi:10.1017/S1461145709000157. PMID 19288974. http://journals.cambridge.org/abstract_S1461145709000157. 
19. ^ Sgaravatti AM, Magnusson AS, Oliveira AS, et al. (June 2009). "Effects of 1,4-butanediol administration on oxidative stress in rat brain: study of the neurotoxicity of gamma-hydroxybutyric acid in vivo". Metabolic Brain Disease 24 (2): 271–82. doi:10.1007/s11011-009-9136-7. ISBN 1101100991367. PMID 19296210. 
20. ^ Madsen U, Ferkany JW, Jones BE, et al. (December 1990). "NMDA receptor agonists derived from ibotenic acid. Preparation, neuroexcitation and neurotoxicity". European Journal of Pharmacology 189 (6): 381–91. doi:10.1016/0922-4106(90)90035-V. PMID 1963602. 
21. ^ Dorph-Petersen, K-A, Pierri, J, Perel, J, Sun, Z, Sampson, A-R and Lewis, D (2005) The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys. Neuropsychopharmacology, 30, 1649–1661