Editing MPTP

{{Short description|Tetrahydropyridine, a chemical causing Parkinson's disease symptoms}}
{{about|the chemical|the mitochondrial pore|Mitochondrial permeability transition}}
{{Distinguish|text=[[MPPP]] or [[MPP+|MPP<sup>+</sup>]]}}
{{chembox
|Verifiedfields = changed
|Watchedfields = changed
|verifiedrevid = 464192606
|ImageFile = MPTP.svg
|ImageSize = 200px
|ImageAlt = Skeletal formula
|ImageFile1 = MPTP molecule ball.png
|ImageSize1 = 210
|ImageAlt1 = Ball-and-stick model of MPTP
|PIN=1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
|Section1={{Chembox Identifiers
|KEGG_Ref = {{keggcite|correct|kegg}}
|KEGG = C04599
|InChI = 1/C12H15N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-7H,8-10H2,1H3
|InChIKey = PLRACCBDVIHHLZ-UHFFFAOYAV
|ChEMBL_Ref = {{ebicite|correct|EBI}}
|ChEMBL = 24172
|UNII_Ref = {{fdacite|changed|FDA}}
|UNII = 9P21XSP91P
|StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|StdInChI = 1S/C12H15N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-7H,8-10H2,1H3
|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
|StdInChIKey = PLRACCBDVIHHLZ-UHFFFAOYSA-N
|CASNo_Ref = {{cascite|correct|CAS}}
|CASNo=28289-54-5
|PubChem=1388
|IUPHAR_ligand = 280
|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
|ChemSpiderID = 1346
|EINECS=248-939-7
|ChEBI_Ref = {{ebicite|correct|EBI}}
|ChEBI = 17963
|SMILES = c2ccccc2/C1=C/CN(C)CC1
|MeSHName = 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
}}
|Section2={{Chembox Properties
|C=12|H=15|N=1
|MeltingPtC= 40
|MeltingPt_ref = <ref>{{cite web | url = http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=DBMaint&actionHandle=default&nextPage=jsp/chemidlite/ResultScreen.jsp&TXTSUPERLISTID=0028289545 | title = 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine | publisher = ChemIDplus}}</ref>
|BoilingPtC= 128 to 132 
|BoilingPt_notes = 12 Torr<ref>{{cite journal | author = Buchi, I. J. | journal = Helvetica Chimica Acta | year = 1952 | volume = 35 | issue = 5 | pages = 1527–1536 | doi = 10.1002/hlca.19520350514 | title = Synthese und analgetische Wirkung einiger 1-Methyl-4-phenyl-piperidin-(4)-alkylsulfone. 1. Mitteilung }}</ref>
|Solubility= Slightly soluble
}}
|Section3={{Chembox Hazards
|NFPA-H = 4
|NFPA-F = 0
|NFPA-R = 0
}}
}}

'''MPTP''' ('''1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine''') is an [[organic compound]]. It is classified as a [[tetrahydropyridine]]. It is of interest as a [[Precursor (chemistry)|precursor]] to the [[monoaminergic neurotoxin]] [[MPP+|MPP<sup>+</sup>]], which causes permanent symptoms of [[Parkinson's disease]] by destroying dopaminergic [[neuron]]s in the [[substantia nigra]] of the [[brain]]. It has been used to study disease models in various animals.<ref>{{cite journal |doi=10.1111/j.1476-5381.2011.01426.x |title=Animal models of Parkinson's disease: A source of novel treatments and clues to the cause of the disease |date=2011 |last1=Duty |first1=Susan |last2=Jenner |first2=Peter |journal=British Journal of Pharmacology |volume=164 |issue=4 |pages=1357–1391 |pmid=21486284 |pmc=3229766 }}</ref><ref>{{cite journal |doi=10.1016/j.neubiorev.2022.104792 |title=The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the cognitive and motor functions in rodents: A systematic review and meta-analysis |date=2022 |last1=Narmashiri |first1=Abdolvahed |last2=Abbaszadeh |first2=Mojtaba |last3=Ghazizadeh |first3=Ali |journal=Neuroscience & Biobehavioral Reviews |volume=140 |page=104792 |pmid=35872230 |s2cid=250929452 }}</ref>

While MPTP itself has no [[psychoactive]] effects, the compound may be accidentally produced during the manufacture of [[MPPP]], a synthetic opioid [[recreational drug use|drug]] with effects similar to those of [[morphine]] and [[pethidine]] (meperidine). The Parkinson-inducing effects of MPTP were first discovered following accidental injection as a result of contaminated MPPP.

==Toxicity==
{{More citations needed|section|date=December 2022}}
Injection of MPTP causes rapid onset of [[Parkinsonism]], hence users of MPPP contaminated with MPTP will develop these symptoms.

MPTP itself is not toxic, but it is a [[lipophilicity|lipophilic]] compound and can therefore cross the [[blood–brain barrier]]. Once inside the brain, MPTP is metabolized into the toxic [[cation]] [[1-methyl-4-phenylpyridinium]] (MPP<sup>+</sup>)<ref>{{cite journal|title=Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat|year=1994|doi=10.1073/pnas.91.11.5104|doi-access=free|last1=Frim|first1=D. M.|last2=Uhler|first2=T. A.|last3=Galpern|first3=W. R.|last4=Beal|first4=M. F.|last5=Breakefield|first5=X. O.|last6=Isacson|first6=O.|journal=Proceedings of the National Academy of Sciences|volume=91|issue=11|pages=5104–5108|pmid=8197193|pmc=43940|bibcode=1994PNAS...91.5104F}}</ref> by the enzyme [[monoamine oxidase B]] (MAO-B) of [[glial cell]]s, specifically astrocytes. MPP<sup>+</sup> kills primarily [[dopaminergic|dopamine-producing]] [[neurons]] in a part of the brain called the [[pars compacta]] of the [[substantia nigra]] (SNc). MPP<sup>+</sup> interferes with [[complex I]] of the [[electron transport chain]], a component of [[mitochondria]]l metabolism, which leads to cell death and causes the buildup of [[free radical]]s, toxic molecules that contribute further to cell destruction.

Because MPTP itself is not directly harmful, toxic effects of acute MPTP poisoning can be mitigated by the administration of [[monoamine oxidase inhibitor]]s (MAOIs) such as [[selegiline]]. MAOIs prevent the metabolism of MPTP to MPP<sup>+</sup> by inhibiting the action of MAO-B, minimizing toxicity, and preventing neural death.

Dopaminergic neurons are selectively vulnerable to MPP<sup>+</sup> because DA neurons exhibit dopamine [[reuptake]] which is mediated by [[dopamine transporter]] (DAT), which also has high-affinity for MPP<sup>+</sup>.<ref>{{cite journal | last1=Richardson | first1=Jason | title=Richardson, Jason R., et al. "Paraquat neurotoxicity is distinct from that of MPTP and rotenone. | url=https://academic.oup.com/toxsci/article-abstract/88/1/193/1662975 | journal=Toxicological Sciences  | year=2005 | volume=88 | issue=1 | pages=193–201 | doi=10.1093/toxsci/kfi304 | pmid=16141438 | doi-access=free}}</ref> The dopamine transporter scavenges for excessive dopamine at the synaptic spaces and transports them back into the cell. Even though this property is exhibited by both VTA and SNc neurons, VTA neurons are protective against MPP<sup>+</sup> insult due to the expression of [[calbindin]]. Calbindin regulates the availability of Ca<sup>2+</sup> within the cell, which is not the case in SNc neurons due to their high-calcium-dependent autonomous pacemaker activity.

The gross depletion of dopaminergic neurons severely affects [[cerebral cortex|cortical]] control of complex movements. The direction of complex movement is based from the substantia nigra to the [[putamen]] and [[caudate nucleus]], which then relay signals to the rest of the brain. This pathway is controlled via dopamine-using neurons, which MPTP selectively destroys, resulting, over time, in parkinsonism.

MPTP causes Parkinsonism in [[primate]]s, including humans. [[Rodent]]s are much less susceptible. Rats are almost immune to the adverse effects of MPTP. Mice were thought to only suffer from cell death in the substantia nigra (to a differing degree according to the strain of mice used) but do not show Parkinsonian symptoms;<ref name="william">{{cite book | author = Langston, J. W. | chapter = Chapter 30 The Impact of MPTP on Parkinson's Disease Research: Past, Present, and Future | title = Parkinson's Disease. Diagnosis and Clinical Management | editor = Factor, S. A. | editor2 = Weiner, W. J. | publisher = Demos Medical Publishing | year = 2002 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK10185/}}</ref> however, most of the recent studies indicate that MPTP can result in Parkinsonism-like syndromes in mice (especially chronic syndromes).<ref>{{cite web | url = http://www.ndineuroscience.com/userfiles/Parkinson's%20info.pdf | title = Parkinson's Disease Models | publisher = Neuro Detective International | access-date = 2012-03-06 }}</ref><ref>{{ cite journal |author1=Luo Qin |author2=Peng Guoguang |author3=Wang Jiacai |author4=Wang Shaojun | year = 2010 | title = The Establishment of Chronic Parkinson's Disease in Mouse Model Induced by MPTP | journal = Journal of Chongqing Medical University | volume = 2010 | issue = 8 | pages = 1149–1151 | url = http://caod.oriprobe.com/articles/24182813/The_establishment_of_chronic_parkinson__s_desease_in_mouse_model_indud.htm | access-date = 2012-03-06}}</ref> It is believed that the lower levels of MAO-B in the rodent brain's capillaries may be responsible for this.<ref name="william"/>

==Discovery in users of illicit drugs==
The neurotoxicity of MPTP was hinted at in 1976 after Barry Kidston, a 23-year-old chemistry graduate student in [[Maryland]], US, synthesized MPPP with MPTP as a major impurity and self-injected the result. Within three days he began exhibiting symptoms of Parkinson's disease. The [[National Institute of Mental Health]] found traces of MPTP and other [[pethidine]] [[structural analog|analogs]] in his lab. They tested the substances on rats, but due to rodents' tolerance for this type of neurotoxin, nothing was observed. Kidston's Parkinsonism was treated with [[levodopa]] but he died 18 months later from a [[cocaine]] overdose. Upon autopsy, [[Lewy body|Lewy bodies]] and destruction of dopaminergic neurons in the substantia nigra were discovered.<ref>{{cite journal | author = Fahn, S. | title = Book Review -- The Case of the Frozen Addicts: How the Solution of an Extraordinary Medical Mystery Spawned a Revolution in the Understanding and Treatment of Parkinson's Disease | journal = The New England Journal of Medicine | year = 1996 | volume = 335 | issue = 26 | pages = 2002–2003 | doi = 10.1056/NEJM199612263352618 }}</ref><ref>{{cite journal | journal = Psychiatry Research |vauthors=Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ | volume = 1 | issue = 3 | date = 1979 | pages = 249–254 | title = Chronic parkinsonism secondary to intravenous injection of meperidine analogs | doi = 10.1016/0165-1781(79)90006-4|pmid=298352 |s2cid=44304872}}</ref>

In 1983, four people in [[Santa Clara County, California]], US, were diagnosed with Parkinsonism after having used MPPP contaminated with MPTP, and as many as 120 were reported to have been diagnosed with Parkinson's symptoms.<ref>{{cite news |title=Bogus Heroin Brings Illness on the Coast |url=https://timesmachine.nytimes.com/timesmachine/1983/12/09/100194.html?zoom=16&pageNumber=20 |access-date=3 September 2023 |work=The New York Times |date=9 December 1983}}</ref> The neurologist [[William Langston|J. William Langston]] in collaboration with NIH tracked down MPTP as the cause, and its effects on primates were researched. After performing neural grafts of fetal tissue on three of the patients at [[Lund University|Lund University Hospital]] in [[Sweden]], the motor symptoms of two of the three patients were successfully treated, and the third showed partial recovery.<ref>{{cite news | url = https://query.nytimes.com/gst/fullpage.html?res=9E0CE7D91030F935A15752C1A964958260 | title = Success reported using fetal tissue to repair a brain | newspaper = [[The New York Times]] | date = 26 November 1992}}</ref><ref>{{cite news|url=https://arstechnica.com/science/2016/05/medical-mystery-how-tainted-drugs-froze-young-people-but-kickstarted-parkinsons-research/|title=How tainted drugs "froze" young people—but kickstarted Parkinson's research|work=[[Ars Technica]]|access-date=21 May 2016}}</ref>

Langston documented the case in his 1995 book ''The Case of the Frozen Addicts'',<ref>{{cite book |last=Langston |first=J. W. |url=https://archive.org/details/caseoffrozenaddi00lang |title=The Case of the Frozen Addicts |author2=Palfreman, J. |date=May 1995 |publisher=[[Pantheon Books]] |isbn=978-0-679-42465-9 |author-link1=William Langston |author-link2=Jon Palfreman |url-access=registration}}</ref> which was later featured in two [[Nova (American TV series)|''NOVA'']] productions by [[Public Broadcasting Service|PBS]], re-aired in the UK on the [[BBC]] science series [[Horizon (UK TV series)|''Horizon'']].<ref>"The Case of the Frozen Addicts" first broadcast 7 April 1986 and "Awakening the Frozen Addicts" first broadcast 4 January 1993. See [[List of Horizon episodes]]</ref>

== Contribution of MPTP to research into Parkinson's disease ==
Langston ''et al.'' (1984) found that injections of MPTP in [[squirrel monkey]]s resulted in Parkinsonism, symptoms of which were subsequently reduced by [[levodopa]], the drug-of-choice in the treatment of Parkinson's disease along with [[carbidopa]] and [[entacapone]]. The symptoms and brain structures of MPTP-induced Parkinson's disease are fairly indistinguishable to the point that MPTP may be used to simulate the disease in order to study Parkinson's disease physiology and possible treatments within the laboratory. Mouse studies have shown that susceptibility to MPTP increases with age.<ref>{{cite journal | last1 = Jackson-Lewis | first1 = V. | last2 = Przedborski | first2 = S. | year = 2007 | title = Protocol for the MPTP Mouse Model of Parkinson's Disease | journal = [[Nature Protocols]] | volume = 2 | issue = 1 | pages = 141–151 | doi = 10.1038/nprot.2006.342 | pmid = 17401348 | s2cid = 39743261}}</ref>

Knowledge of MPTP and its use in reliably recreating Parkinson's disease symptoms in experimental models has inspired scientists to investigate the possibilities of surgically replacing neuron loss through fetal tissue implants, [[subthalamus|subthalamic]] [[deep brain stimulation|electrical stimulation]] and [[stem cell]] research, all of which have demonstrated initial provisional successes.

It has been postulated that Parkinson's disease may be caused by minute amounts of MPP<sup>+</sup>-like compounds from ingestion or exogenously through repeated exposure and that these substances are too minute to be detected significantly by epidemiological studies.<ref>{{ cite web|url=http://www.silsoe.cranfield.ac.uk/ieh/pdf/w21.pdf |title=Pesticides and Parkinson's Disease - A Critical Review |publisher=Institute of Environment and Health, [[Cranfield University]] |date=October 2005 |url-status=dead |archive-url=https://web.archive.org/web/20080227162019/http://www.silsoe.cranfield.ac.uk/ieh/pdf/w21.pdf |archive-date=February 27, 2008 }}</ref>

In 2000, another animal model for Parkinson's disease was found. It was shown that the [[pesticide]] and [[insecticide]] [[rotenone]] causes Parkinsonism in rats by killing dopaminergic neurons in the substantia nigra. Like MPP<sup>+</sup>, rotenone also interferes with [[complex I]] of the [[electron transport chain]].<ref>{{cite web|url=http://www.ninds.nih.gov/funding/research/parkinsonsweb/greenamyre_summary.htm |title=Summary of the Article by Dr. Greenamyre on Pesticides and Parkinson's Disease |publisher=National Institute of Neurological Disorders and Stroke |date=9 February 2005 |url-status=dead |archive-url=https://web.archive.org/web/20071016034842/http://www.ninds.nih.gov/funding/research/parkinsonsweb/greenamyre_summary.htm |archive-date=October 16, 2007}}</ref>

==Synthesis and uses==
MPTP was first synthesized as a potential [[analgesic]] in 1947 by Ziering ''et al.'' by reaction of [[phenylmagnesium bromide]] with [[1-methyl-4-piperidinone]].<ref>{{cite journal | journal = Journal of Organic Chemistry | year = 1947 | volume = 12 | issue = 6 | pages = 885–893 | title = Piperidine Derivatives. Part II. 2-Phenyl- and 2-Phenylalkyl-Piperidines |author1=Lee, J. |author2=Ziering, A. |author3=Heineman, S. D. |author4=Berger, L. | doi = 10.1021/jo01170a021 | pmid = 18919741 }}</ref> It was tested as a treatment for various conditions, but the tests were halted when Parkinson-like symptoms were noticed in monkeys. In one test of the substance, two of six human subjects died.<ref name="vinken">{{cite book |author1=Vinken, P. J. |author2=Bruyn, G. W. | title = Intoxications of the Nervous System | page = 369 | publisher = Elsevier Health Sciences | year = 1994 | isbn = 978-0-444-81284-1}}</ref>

MPTP is used in industry as a chemical intermediate; the [[chloride]] of the toxic metabolite MPP<sup>+</sup>, [[cyperquat]], has been used as a [[herbicide]].<ref name="vinken" /> While cyperquat is not used anymore, the closely related substance [[paraquat]] is still being used as a herbicide in some countries.

==Analogues==
[[Structural analog|Analogue]]s of MPTP include [[2′-NH2-MPTP|2′-NH<sub>2</sub>-MPTP]] (2′-amino-MPTP) and [[2′-CH3-MPTP|2′-CH<sub>3</sub>-MPTP]] (2′-methyl-MPTP).<ref name="MaretTestaJenner1990">{{cite journal | vauthors = Maret G, Testa B, Jenner P, el Tayar N, Carrupt PA | title = The MPTP story: MAO activates tetrahydropyridine derivatives to toxins causing parkinsonism | journal = Drug Metab Rev | volume = 22 | issue = 4 | pages = 291–332 | date = 1990 | pmid = 2253555 | doi = 10.3109/03602539009041087 | url = }}</ref><ref name="ManayeSonsallaBarnett1989">{{cite journal | vauthors = Manaye KF, Sonsalla PK, Barnett G, Heikkila RE, Woodward DJ, Smith WK, German DC | title = 1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP)-induced degeneration of mesostriatal dopaminergic neurons in the mouse: biochemical and neuroanatomical studies | journal = Brain Res | volume = 491 | issue = 2 | pages = 307–315 | date = July 1989 | pmid = 2765888 | doi = 10.1016/0006-8993(89)90065-6 | url = }}</ref><ref name="AndrewsMurphy1993">{{cite journal | vauthors = Andrews AM, Murphy DL | title = Sustained depletion of cortical and hippocampal serotonin and norepinephrine but not striatal dopamine by 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP): a comparative study with 2'-CH3-MPTP and MPTP | journal = J Neurochem | volume = 60 | issue = 3 | pages = 1167–1170 | date = March 1993 | pmid = 8094744 | doi = 10.1111/j.1471-4159.1993.tb03271.x | url = }}</ref>

The [[haloperidol]]-derived monoaminergic neurotoxins [[HPTP]] and [[HPP+|HPP<sup>+</sup>]] are structurally related to MPTP.<ref name="CastagnoliCastagnoliVanderSchyf1999">{{cite journal | vauthors = Castagnoli N, Castagnoli KP, Van der Schyf CJ, Usuki E, Igarashi K, Steyn SJ, Riker RR | title = Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins | journal = Pol J Pharmacol | volume = 51 | issue = 1 | pages = 31–38 | date = 1999 | pmid = 10389142 | doi = | url = }}</ref>

==In popular culture==
* In the novel ''[[Neuromancer]]'', authored by [[William Gibson]], MPTP is used as a means of inducing Parkinsonism in another character. 
	
* MPTP-induced Parkinson's disease is featured in the ''[[Law & Order]]'' episode "[[Law & Order (season 10)#Episodes|Stiff]]."

* In Roger Williams' novel ''[[The Metamorphosis of Prime Intellect]]'' the protagonist administers MPTP to the anti-heroine’s former nurse, who had stolen her painkillers in life, doing so as a means of neurodegenerative torture.

== See also ==
* [[Phenindamine]]
* [[6-Hydroxydopamine]]
* [[Norsalsolinol]]

==References==
{{reflist}}

==External links==
*{{cite journal |title= Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis. |journal= Science |volume= 219 |issue= 4587 |pages= 979–980 |date=25 February 1983 |jstor = 1690734|last1 = Langston|first1 = J. William|last2= Ballard |first2= Philip |last3= Tetrud |first3= James W. |last4= Irwin |first4= Ian |doi= 10.1126/science.6823561 |pmid= 6823561 |bibcode= 1983Sci...219..979L |s2cid= 31966839 }}
*{{cite news |url= http://www.time.com/time/archive/preview/0,10987,1101850408-141542,00.html |archive-url= https://web.archive.org/web/20050330194057/http://www.time.com/time/archive/preview/0,10987,1101850408-141542,00.html |url-status= dead |archive-date= March 30, 2005 |title= Surprising Clue to Parkinson's |newspaper=  Time Magazine |date= 24 June 2001 }}
*{{cite news |url= https://www.wired.com/medtech/drugs/news/2007/09/parkinsons_prisoner2 |title= How a Junkie's Brain Helps Parkinson's Patients |newspaper= Wired |date= 21 September 2007 }}
*[http://www.erowid.org/chemicals/mptp/mptp.shtml Erowid MPTP Vault] - Contains information regarding MPTP as a neurotoxin
*[https://www.youtube.com/watch?v=tqj33HXhC0M PBS ''NOVA'' episode, "The Case of the Frozen Addict"]https://openvault.wgbh.org/catalog/V_474CF2C8A20B4173988486AC4C605A3C
*[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345642/ "The MPTP Story" by J. William Langston]. nih.gov.

{{Monoamine neurotoxins}}
{{Authority control}}

[[Category:Prodrugs]]
[[Category:Tetrahydropyridines]]
[[Category:Phenyl compounds]]
[[Category:Monoaminergic neurotoxins]]