MPTP
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Preferred IUPAC name
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine | |
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100.044.475 |
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KEGG | |
MeSH | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
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CompTox Dashboard (EPA)
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Properties | |
C12H15N | |
Molar mass | 173.259 g·mol−1 |
Melting point | 40 °C (104 °F; 313 K)[2] |
Boiling point | 128 to 132 °C (262 to 270 °F; 401 to 405 K) 12 Torr[1] |
Slightly soluble | |
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NFPA 704 (fire diamond) | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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 to the neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study disease models in various animals.[3][4]
While MPTP itself has no
(meperidine). The Parkinson-inducing effects of MPTP were first discovered following accidental injection as a result of contaminated MPPP.Toxicity
This section needs additional citations for verification. (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
Because MPTP itself is not directly harmful, toxic effects of acute MPTP poisoning can be mitigated by the administration of monoamine oxidase inhibitors (MAOIs) such as selegiline. MAOIs prevent the metabolism of MPTP to MPP+ by inhibiting the action of MAO-B, minimizing toxicity, and preventing neural death.
Dopaminergic neurons are selectively vulnerable to MPP+ because DA neurons exhibit dopamine reuptake which is mediated by DAT, which also has high-affinity for MPP+.[6] 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+ insult due to the expression of calbindin. Calbindin regulates the availability of Ca2+ 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 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 primates, including humans. Rodents 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;[7] however, most of the recent studies indicate that MPTP can result in Parkinsonism-like syndromes in mice (especially chronic syndromes).[8][9] It is believed that the lower levels of MAO-B in the rodent brain's capillaries may be responsible for this.[7]
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
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.[12] The neurologist 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 Hospital in Sweden, the motor symptoms of two of the three patients were successfully treated, and the third showed partial recovery.[13][14]
Langston documented the case in his 1995 book The Case of the Frozen Addicts,
Contribution of MPTP to research into Parkinson's disease
Langston et al. (1984) found that injections of MPTP in
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, subthalamic 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+-like compounds from ingestion or exogenously through repeated exposure and that these substances are too minute to be detected significantly by epidemiological studies.[18]
In 2000, another animal model for Parkinson's disease was found. It was shown that the
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.[20] 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.[21]
MPTP is used in industry as a chemical intermediate; the
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 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
- .
- ^ "1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine". ChemIDplus.
- PMID 21486284.
- S2CID 250929452.
- PMID 8197193.
- PMID 16141438.
- ^ a b Langston, J. W. (2002). "Chapter 30 The Impact of MPTP on Parkinson's Disease Research: Past, Present, and Future". In Factor, S. A.; Weiner, W. J. (eds.). Parkinson's Disease. Diagnosis and Clinical Management. Demos Medical Publishing.
- ^ "Parkinson's Disease Models" (PDF). Neuro Detective International. Retrieved 2012-03-06.
- ^ Luo Qin; Peng Guoguang; Wang Jiacai; Wang Shaojun (2010). "The Establishment of Chronic Parkinson's Disease in Mouse Model Induced by MPTP". Journal of Chongqing Medical University. 2010 (8): 1149–1151. Retrieved 2012-03-06.
- .
- S2CID 44304872.
- ^ "Bogus Heroin Brings Illness on the Coast". The New York Times. 9 December 1983. Retrieved 3 September 2023.
- ^ "Success reported using fetal tissue to repair a brain". The New York Times. 26 November 1992.
- ^ "How tainted drugs "froze" young people—but kickstarted Parkinson's research". Ars Technica. Retrieved 21 May 2016.
- ISBN 978-0-679-42465-9.
- List of Horizon episodes
- S2CID 39743261.
- ^ "Pesticides and Parkinson's Disease - A Critical Review" (PDF). Institute of Environment and Health, Cranfield University. October 2005. Archived from the original (PDF) on February 27, 2008.
- ^ "Summary of the Article by Dr. Greenamyre on Pesticides and Parkinson's Disease". National Institute of Neurological Disorders and Stroke. 9 February 2005. Archived from the original on October 16, 2007.
- PMID 18919741.
- ^ ISBN 978-0-444-81284-1.
External links
- Langston, J. William; Ballard, Philip; Tetrud, James W.; Irwin, Ian (25 February 1983). "Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis". Science. 219 (4587): 979–980. S2CID 31966839.
- "Surprising Clue to Parkinson's". Time Magazine. 24 June 2001. Archived from the original on March 30, 2005.
- "How a Junkie's Brain Helps Parkinson's Patients". Wired. 21 September 2007.
- Erowid MPTP Vault - Contains information regarding MPTP as a neurotoxin
- PBS NOVA episode, "The Case of the Frozen Addict"https://openvault.wgbh.org/catalog/V_474CF2C8A20B4173988486AC4C605A3C
- "The MPTP Story" by J. William Langston. nih.gov.