View source for Neurotoxicity

{{short description|Toxic effects on the nervous system}}
{{More footnotes|date=August 2014}}

'''Neurotoxicity''' is a form of [[toxicity]] in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the [[central nervous system|central]] and/or [[peripheral nervous system]].<ref name="Neurotoxicity review">{{cite journal |last1=Cunha-Oliveira |first1=Teresa |last2=Rego |first2=Ana Cristina |last3=Oliveira |first3=Catarina R. |title=Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs |journal=Brain Research Reviews |date=June 2008 |volume=58 |issue=1 |pages=192–208 |doi=10.1016/j.brainresrev.2008.03.002 |pmid=18440072 |hdl=10316/4676 |s2cid=17447665 |hdl-access=free }}</ref> It occurs when exposure to a substance – specifically, a [[neurotoxin]] or [[neurotoxicant]]– alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to [[nervous tissue]].<ref name="Neurotoxicity review" /> This can eventually disrupt or even kill [[neuron]]s, which are cells that [[neurotransmission|transmit and process signals]] in the brain and other parts of the nervous system. Neurotoxicity can result from [[organ transplant]]s, [[radiation treatment]], certain [[drug therapy|drug therapies]], [[recreational drug use]], exposure to [[heavy metals]], bites from certain species of [[venomous snake]]s, [[pesticide]]s,<ref>{{cite journal |last1=Keifer |first1=Matthew C. |last2=Firestone |first2=Jordan |title=Neurotoxicity of Pesticides |journal=Journal of Agromedicine |date=31 July 2007 |volume=12 |issue=1 |pages=17–25 |doi=10.1300/J096v12n01_03 |pmid=18032333 |s2cid=23069667 }}</ref><ref>{{cite journal |last1=Costa |first1=Lucio, G. |last2=Giordano |first2=G |last3=Guizzetti |first3=M |last4=Vitalone |first4=A |title=Neurotoxicity of pesticides: a brief review |journal=Frontiers in Bioscience |date=2008 |volume=13 |issue=13 |pages=1240–9 |doi=10.2741/2758 |pmid=17981626 |s2cid=36137987 |doi-access=free }}</ref> certain industrial cleaning [[solvent]]s,<ref>{{cite book |doi=10.1016/B978-0-444-62627-1.00007-X |chapter=Neurotoxicity of solvents |title=Occupational Neurology |series=Handbook of Clinical Neurology |year=2015 |last1=Sainio |first1=Markku Alarik |volume=131 |pages=93–110 |pmid=26563785 |isbn=978-0-444-62627-1 }}</ref> fuels<ref>{{cite journal |last1=Ritchie |first1=Glenn D. |last2=Still |first2=Kenneth R. |last3=Alexander |first3=William K. |last4=Nordholm |first4=Alan F. |last5=Wilson |first5=Cody L. |last6=Rossi III |first6=John |last7=Mattie |first7=David R. |title=A review of the neurotoxicity risk of selected hydrocarbon fuels |journal=Journal of Toxicology and Environmental Health Part B: Critical Reviews |date=1 July 2001 |volume=4 |issue=3 |pages=223–312 |doi=10.1080/109374001301419728 |pmid=11503417 |bibcode=2001JTEHB...4..223R }}</ref> and certain naturally occurring substances.  Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Chronic mold exposure in homes can lead to neurotoxicity which may not appear for months to years of exposure.<ref>{{cite journal |last1=Curtis |first1=Luke |last2=Lieberman |first2=Allan |last3=Stark |first3=Martha |last4=Rea |first4=William |last5=Vetter |first5=Marsha |title=Adverse Health Effects of Indoor Molds |journal=Journal of Nutritional & Environmental Medicine |date=September 2004 |volume=14 |issue=3 |pages=261–274 |doi=10.1080/13590840400010318 }}</ref> All symptoms listed above are consistent with mold mycotoxin accumulation.<ref>{{cite book |doi=10.1016/S0065-2164(04)55013-X |title=Role of Molds and Mycotoxins in Being Sick in Buildings: Neurobehavioral and Pulmonary Impairment |series=Advances in Applied Microbiology |year=2004 |last1=Kilburn |first1=Kaye H. |volume=55 |pages=339–359 |pmid=15350801 |isbn=978-0-12-002657-9 }}</ref>

The term ''neurotoxicity'' implies the involvement of a neurotoxin; however, the term ''neurotoxic'' may be used more loosely to describe states that are known to cause physical [[brain damage]], but where no specific neurotoxin has been identified.<ref>{{Citation |last=Risk |first=National Research Council (US) Committee on Neurotoxicology and Models for Assessing |title=Introduction: Defining the Problem of Neurotoxicity |date=1992 |work=Environmental Neurotoxicology |url=https://www.ncbi.nlm.nih.gov/books/NBK234243/ |access-date=2025-09-16 |publisher=National Academies Press (US) |language=en}}</ref>

The presence of [[neurocognitive deficit]]s alone is not usually considered sufficient evidence of neurotoxicity, as many substances may impair [[neurocognitive]] performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is [[drug elimination|eliminated]] from the body.<ref>{{Cite journal |last=Choi |first=D |date=1988 |title=Glutamate neurotoxicity and diseases of the nervous system |url=https://linkinghub.elsevier.com/retrieve/pii/0896627388901626 |journal=Neuron |language=en |volume=1 |issue=8 |pages=623–634 |doi=10.1016/0896-6273(88)90162-6|url-access=subscription }}</ref> In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods.<ref>{{Cite web |title=Toxicology |url=https://www.niehs.nih.gov/health/topics/science/toxicology |access-date=2025-09-16 |website=National Institute of Environmental Health Sciences |language=en}}</ref><ref>{{Citation |last=Rohlman |first=Diane S. |title=Chapter Six - Identifying and preventing the neurotoxic effects of pesticides |date=2022-01-01 |work=Advances in Neurotoxicology |volume=7 |pages=203–255 |editor-last=Lucchini |editor-first=Roberto G. |url=https://www.sciencedirect.com/science/article/pii/S2468748022000078 |access-date=2025-09-16 |series=Occupational Neurotoxicology |publisher=Academic Press |doi=10.1016/bs.ant.2022.05.001 |last2=Olson |first2=James R. |last3=Ismail |first3=Ahmed A. |last4=Bonner |first4=Matthew R. |last5=Abdel Rasoul |first5=Gaafar |last6=Hendy |first6=Olfat |editor2-last=Aschner |editor2-first=Michael |editor3-last=Costa |editor3-first=Lucio G.|url-access=subscription }}</ref> Some of the most common naturally occurring brain toxins that lead to neurotoxicity as a result of long term drug use are [[amyloid beta]] (Aβ), [[glutamate]], [[dopamine]], and [[oxygen radicals]]. When present in high concentrations, they can lead to neurotoxicity and death ([[apoptosis]]). Some of the symptoms that result from cell death include loss of motor control, cognitive deterioration and autonomic nervous system dysfunction. Additionally, neurotoxicity has been found to be a major cause of [[neurodegenerative diseases]] such as [[Alzheimer's disease]] (AD).{{fact|date=March 2021}}<ref>{{Cite journal |last1=Bariweni |first1=Moses W |last2=Kamenebali |first2=Iyele |last3=Bedford |first3=Denyefa, Johnson |date=2024-04-15 |title=Metronidazole-induced neurotoxicity: Possible central serotonergic and noradrenergic system involvement |url=https://pharmacoj.com/ojs/index.php/Medph/article/view/74 |journal=Medical and Pharmaceutical Journal |volume=3 |issue=1 |pages=22–34 |doi=10.55940/medphar202474|doi-access=free }}</ref>

==Neurotoxic agents==

===Amyloid beta===
[[Amyloid beta]] (Aβ) was found to cause neurotoxicity and cell death in the brain when present in high concentrations. Aβ results from a mutation that occurs when protein chains are cut at the wrong locations, resulting in chains of different lengths that are unusable. Thus they are left in the brain until they are broken down, but if enough accumulate, they form [[Senile plaques|plaques]] which are toxic to [[neurons]]. Aβ uses several routes in the [[central nervous system]] to cause cell death. An example is through the [[nicotinic acetylcholine receptor]] (nAchRs), which is a receptor commonly found along the surfaces of the cells that respond to nicotine stimulation, turning them on or off. Aβ was found manipulating the level of [[nicotine]] in the brain along with the [[MAP kinase]], another signaling receptor, to cause cell death. Another chemical in the brain that Aβ regulates is [[JNK]]; this chemical halts the [[extracellular signal-regulated kinases]] (ERK) pathway, which normally functions as memory control in the brain. As a result, this memory favoring pathway is stopped, and the brain loses essential memory function. The loss of memory is a symptom of [[neurodegenerative disease]], including AD. Another way Aβ causes cell death is through the [[Protein phosphorylation|phosphorylation]] of [[AKT]]; this occurs as the phosphate group is bound to several sites on the protein. This phosphorylation allows AKT to interact with [[Bcl-2-associated death promoter|BAD]], a protein known to cause cell death. Thus an increase in Aβ results in an increase of the AKT/BAD complex, in turn stopping the action of the anti-apoptotic protein [[Bcl-2]], which normally functions to stop cell death, causing accelerated neuron breakdown and the progression of AD.{{fact|date=March 2021}}

===Glutamate===
[[Glutamate]] is a chemical found in the brain that poses a toxic threat to [[neuron]]s when found in high concentrations. This concentration equilibrium is extremely delicate and is usually found in millimolar amounts extracellularly. When disturbed, an accumulation of glutamate occurs as a result of a mutation in the [[glutamate transporters]], which act like pumps to clear glutamate from the synapse. This causes glutamate concentration to be several times higher in the blood than in the brain; in turn, the body must act to maintain equilibrium between the two concentrations by pumping the glutamate out of the bloodstream and into the neurons of the brain. In the event of a mutation, the glutamate transporters are unable to pump the glutamate back into the cells; thus a higher concentration accumulates at the [[glutamate receptors]]. This opens the ion channels, allowing calcium to enter the cell causing excitotoxicity.  Glutamate results in cell death by turning on the [[N-methyl-D-aspartic acid]] receptors (NMDA); these receptors cause an increased release of calcium ions (Ca<sup>2+</sup>) into the cells. As a result, the increased concentration of Ca<sup>2+</sup> directly increases the stress on [[mitochondria]], resulting in excessive [[oxidative phosphorylation]] and production of [[reactive oxygen species]] (ROS) via the activation of [[nitric oxide synthase]], ultimately leading to cell death. Aβ was also found aiding this route to neurotoxicity by enhancing neuron vulnerability to glutamate.{{fact|date=March 2021}}

===Oxygen radicals===
The formation of [[oxygen radicals]] in the brain is achieved through the [[nitric oxide synthase]] (NOS) pathway. This reaction occurs as a response to an increase in the Ca<sup>2+</sup> concentration inside a brain cell. This interaction between the Ca<sup>2+</sup> and NOS results in the formation of the cofactor [[tetrahydrobiopterin]] (BH4), which then moves from the plasma membrane into the cytoplasm. As a final step, NOS is dephosphorylated yielding [[nitric oxide]] (NO), which accumulates in the brain, increasing its [[oxidative stress]]. There are several ROS, including [[superoxide]], [[hydrogen peroxide]] and [[hydroxyl]], all of which lead to neurotoxicity. Naturally, the body utilizes a defensive mechanism to diminish the fatal effects of the reactive species by employing certain enzymes to break down the ROS into small, benign molecules of simple oxygen and water. However, this breakdown of the ROS is not completely efficient; some reactive residues are left in the brain to accumulate, contributing to neurotoxicity and cell death. The brain is more vulnerable to oxidative stress than other organs, due to its low oxidative capacity. Because [[neuron]]s are characterized as [[postmitotic]] cells, meaning that they live with accumulated damage over the years, accumulation of ROS is fatal. Thus, increased levels of ROS age neurons, which leads to accelerated neurodegenerative processes and ultimately the advancement of AD.

=== Dopaminergic Neurotoxicity ===

==== Endogenous ====
The endogenously produced autotoxin metabolite of dopamine, [[3,4-Dihydroxyphenylacetaldehyde]] (DOPAL), is a potent inducer of programmed cell death (apoptosis) in dopaminergic neurons.<ref>{{Cite journal |last1=Kristal |first1=B. S. |last2=Conway |first2=A. D. |last3=Brown |first3=A. M. |last4=Jain |first4=J. C. |last5=Ulluci |first5=P. A. |last6=Li |first6=S. W. |last7=Burke |first7=W. J. |date=2001-04-15 |title=Selective dopaminergic vulnerability: 3,4-dihydroxyphenylacetaldehyde targets mitochondria |journal=Free Radical Biology & Medicine |volume=30 |issue=8 |pages=924–931 |doi=10.1016/s0891-5849(01)00484-1 |issn=0891-5849 |pmid=11295535}}</ref> DOPAL may play an important role in the pathology of [[Parkinson's disease]].<ref>{{Cite journal |last1=Goldstein |first1=David S. |last2=Sullivan |first2=Patti |last3=Holmes |first3=Courtney |last4=Miller |first4=Gary W. |last5=Alter |first5=Shawn |last6=Strong |first6=Randy |last7=Mash |first7=Deborah C. |last8=Kopin |first8=Irwin J. |last9=Sharabi |first9=Yehonatan |date=September 2013 |title=Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease |journal=Journal of Neurochemistry |volume=126 |issue=5 |pages=591–603 |doi=10.1111/jnc.12345 |issn=1471-4159 |pmc=4096629 |pmid=23786406}}</ref><ref>{{Cite journal |last1=Masato |first1=Anna |last2=Plotegher |first2=Nicoletta |last3=Boassa |first3=Daniela |last4=Bubacco |first4=Luigi |date=2019-08-20 |title=Impaired dopamine metabolism in Parkinson's disease pathogenesis |journal=Molecular Neurodegeneration |volume=14 |issue=1 |pages=35 |doi=10.1186/s13024-019-0332-6 |issn=1750-1326 |pmc=6728988 |pmid=31488222 |doi-access=free }}</ref>

==== Drug induced ====
Certain drugs, most famously the [[pesticide]] and metabolite [[MPP+|MPP+ (1-methyl-4-phenylpyridin-1-ium)]] can induce [[Parkinson's disease]] by destroying dopaminergic neurons in the [[substantia nigra]].<ref name=":1" /> MPP+ interacts with the [[electron transport chain]] in the [[Mitochondrion|mitochondria]] to generate [[reactive oxygen species]] which cause generalized [[Oxidative stress|oxidative damage]] and ultimately cell death.<ref name=":2" /><ref name=":3">{{Cite journal|last1=Jackson-Lewis|first1=Vernice|last2=Przedborski|first2=Serge|date=Jan 2007|title=Protocol for the MPTP mouse model of Parkinson's disease|url=https://www.nature.com/articles/nprot.2006.342|journal=Nature Protocols|language=en|volume=2|issue=1|pages=141–151|doi=10.1038/nprot.2006.342|pmid=17401348|s2cid=39743261|issn=1750-2799|url-access=subscription}}</ref> MPP+ is produced by [[monoamine oxidase B]] as a metabolite of [[MPTP|MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)]], and its toxicity is particularly significant to dopaminergic neurons because of an [[Active transport|active transporter]] on those cells that bring it into the cytoplasm.<ref name=":3" /> The neurotoxicity of MPP+ was first investigated after MPTP was produced as a contaminant in the [[pethidine]] synthesized by a chemistry graduate student, who injected the contaminated drug and developed overt Parkinson's within weeks.<ref name=":2">{{Cite book|last=Langston|first=J. W.|title=The case of the frozen addicts|date=1995|publisher=Pantheon Books|others=Jon Palfreman|isbn=0-679-42465-2|edition=1|location=New York|oclc=31608154}}</ref><ref name=":1">{{Cite book |last1=Factor |first1=Stewart A. |title=Parkinson's disease : diagnosis and clinical management |last2=Weiner |first2=William J. |date=2008 |publisher=Demos |isbn=978-1-934559-87-1 |edition=2 |location=New York |oclc=191726483}}</ref> Discovery of the mechanism of toxicity was an important advance in the study of Parkinson's disease, and the compound is now used to induce the disease in research animals.<ref name=":1" /><ref name=":0">{{Cite journal|last=Fahn|first=Stanley|date=1996-12-26|title=Book Review|url=https://doi.org/10.1056/NEJM199612263352618|journal=New England Journal of Medicine|volume=335|issue=26|pages=2002–2003|doi=10.1056/NEJM199612263352618|issn=0028-4793|url-access=subscription}}</ref>

==Prognosis==
The prognosis depends upon the length and degree of exposure and the severity of neurological injury. In some instances, exposure to neurotoxins or neurotoxicants can be fatal. In others, patients may survive but not fully recover. In other situations, many individuals recover completely after treatment.<ref>{{cite book |author=National Research Council |title=Environmental Neurotoxicology |date=1992 |isbn=978-0-309-04531-5 |url=https://www.nap.edu/catalog/1801/environmental-neurotoxicology }}{{pn|date=March 2021}}</ref>

The word ''neurotoxicity'' ({{IPAc-en|ˌ|n|ʊər|oʊ-|t|ɒ|k|ˈ|s|ɪ|s|ᵻ|t|i}}) uses [[classical compound|combining forms]] of ''[[wikt:neuro-#Prefix|neuro-]]'' + ''[[wikt:tox-#Prefix|tox-]]'' + ''[[wikt:-icity#Suffix|-icity]]'', yielding "[[nervous tissue]] poisoning".

==See also==
{{col div|colwidth=30em}}
* [[Batrachotoxin]]
* [[Cytotoxicity]]
* [[Multiple chemical sensitivity]]
* [[Nephrotoxicity]]
* [[Ototoxicity]]
* [[Penitrem A]]
* [[Excitotoxicity]]
* [[Toxicity]]
{{colend}}

==References==
{{Reflist}}

==Further reading==
{{Scholia}}
*{{cite journal |last1=Akaike |first1=Akinori |last2=Takada-Takatori |first2=Yuki |last3=Kume |first3=Toshiaki |last4=Izumi |first4=Yasuhiko |title=Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors: Role of α4 and α7 Receptors in Neuroprotection |journal=Journal of Molecular Neuroscience |date=January 2010 |volume=40 |issue=1–2 |pages=211–216 |doi=10.1007/s12031-009-9236-1 |pmid=19714494 |s2cid=7279060 }}
*{{cite journal |last1=Buckingham |first1=Steven D. |last2=Jones |first2=Andrew K. |last3=Brown |first3=Laurence A. |last4=Sattelle |first4=David B. |title=Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection |journal=Pharmacological Reviews |date=March 2009 |volume=61 |issue=1 |pages=39–61 |doi=10.1124/pr.108.000562 |pmid=19293145 |pmc=2830120 }}
*{{cite journal |last1=Huber |first1=Anke |last2=Stuchbury |first2=Grant |last3=Burkle |first3=Alexander |last4=Burnell |first4=Jim |last5=Munch |first5=Gerald |title=Neuroprotective Therapies for Alzheimers Disease |journal=Current Pharmaceutical Design |date=1 February 2006 |volume=12 |issue=6 |pages=705–717 |doi=10.2174/138161206775474251 |pmid=16472161 }}
*{{cite journal |last1=Takada-Takatori |first1=Yuki |last2=Kume |first2=Toshiaki |last3=Izumi |first3=Yasuhiko |last4=Ohgi |first4=Yuta |last5=Niidome |first5=Tetsuhiro |last6=Fujii |first6=Takeshi |last7=Sugimoto |first7=Hachiro |last8=Akaike |first8=Akinori |title=Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation |journal=Biological & Pharmaceutical Bulletin |date=2009 |volume=32 |issue=3 |pages=318–324 |doi=10.1248/bpb.32.318 |pmid=19252271 |doi-access=free }}
*{{cite journal |last1=Takada-Takatori |first1=Yuki |last2=Kume |first2=Toshiaki |last3=Sugimoto |first3=Mitsuhiro |last4=Katsuki |first4=Hiroshi |last5=Sugimoto |first5=Hachiro |last6=Akaike |first6=Akinori |title=Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade |journal=Neuropharmacology |date=September 2006 |volume=51 |issue=3 |pages=474–486 |doi=10.1016/j.neuropharm.2006.04.007 |pmid=16762377 |s2cid=31409248 }}
*{{cite journal |last1=Shimohama |first1=Shun |title=Nicotinic Receptor-Mediated Neuroprotection in Neurodegenerative Disease Models |journal=Biological & Pharmaceutical Bulletin |date=2009 |volume=32 |issue=3 |pages=332–336 |doi=10.1248/bpb.32.332 |pmid=19252273 |doi-access=free }}
*{{cite book |doi=10.1016/B978-032305260-3.50037-X |chapter=Neurotoxic Effects of Pharmaceutical Agents II: Psychiatric Agents |title=Clinical Neurotoxicology |year=2009 |last1=Ryan |first1=Melody |last2=Kennedy |first2=Kara A. |pages=348–357 |isbn=978-0-323-05260-3 }}
* {{cite journal |last1=Lerner |first1=David P. |last2=Tadevosyan |first2=Aleksey |last3=Burns |first3=Joseph D. |title=Toxin-Induced Subacute Encephalopathy |journal=Neurologic Clinics |date=1 November 2020 |volume=38 |issue=4 |pages=799–824 |doi=10.1016/j.ncl.2020.07.006 |pmid=33040862 |s2cid=222301922 }}

{{Neurotoxins}}
{{Monoamine neurotoxins}}
[[Category:Neurological disorders]]
[[Category:Toxicology]]