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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/04/19 10:57:28」(JST)

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This article is about the chemical. For the mitochondrial pore, see mitochondrial permeability transition.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin precursor to 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 animal studies.

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

Toxicity

Injection of MPTP causes rapid onset of Parkinsonism, hence users of MPPP contaminated with MPTP will develop these symptoms.

MPTP itself is not toxic, and as a lipophilic compound can cross the blood–brain barrier. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+) by the enzyme MAO-B of glial cells. MPP+ kills primarily dopamine-producing neurons in a part of the brain called the pars compacta of the substantia nigra. MPP+ interferes with complex I of the electron transport chain, a component of mitochondrial metabolism, which leads to cell death and causes the buildup of free radicals, 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 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.

MPP+ has quite selective abilities to cause neuronal death in dopaminergic cells, it is presumed through a high-affinity uptake process in nerve terminals normally used to reuptake dopamine after it has been released into the synaptic cleft. The dopamine transporter moves MPP+ inside the cell.

The resulting gross depletion of dopaminergic neurons has severe implications on 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 differing degree according to the strain of mice used) but do not show Parkinsonian symptoms,^[1] however most of the recent studies indicate that MPTP can result in Parkinsonism-like syndromes in mice (especially chronic syndromes).^[2]^[3] It is believed that the lower levels of MAO-B in the rodent brain's capillaries may be responsible for this.^[1]

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 analogues 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 successfully treated with levodopa but he died 18 months later from a cocaine overdose. Upon autopsy, destruction of dopaminergic neurons in the substantia nigra was discovered.^[4]

In 1982, seven people in Santa Clara County, California, US, were diagnosed with Parkinsonism after having used MPPP contaminated with MPTP. The neurologist J. William Langston in collaboration with NIH tracked down MPTP as the cause, and its effects on primates were researched. The motor symptoms of two of the seven patients were eventually successfully treated at Lund University Hospital in Sweden with neural grafts of fetal tissue.^[5]

Langston documented the case in his 1995 book The Case of the Frozen Addicts, which was later featured in two NOVA productions by PBS.^[6]

Contribution of MPTP to research into Parkinson's disease

Langston et al.(1984) found that injections of MPTP in squirrel monkeys resulted in parkinsonism, symptoms of which were subsequently reduced by levodopa, a precursor for the neurotransmitter dopamine, currently the drug-of-choice in treatment of Parkinson's. The symptoms and brain structures of MPTP-induced Parkinson's are fairly indistinguishable to the point that MPTP may be used to simulate the disease in order to study Parkinson's physiology and possible treatments within the laboratory. Mouse studies have shown that susceptibility to MPTP increases with age.^[7]

Knowledge of MPTP and its use in reliably recreating Parkinson's disease 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.^[8]

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+, rotenone also interferes with complex I of the electron transport chain.^[9]

Synthesis and uses

MPTP was first synthesized as an analgesic in 1947 by Ziering et al. by reaction of phenylmagnesium bromide with 1-methyl-4-piperidinone.^[10] 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.^[11]

MPTP is used in industry as a chemical intermediate; the chloride of the toxic metabolite MPP+ was turned into the herbicide cyperquat.^[11]

In popular culture

In the novel Neuromancer, authored by William Gibson, MPTP is used as a means of inducing parkinsonism to a character. Although the book was published in 1984, shortly after deleterious effects of this compound were first described, it depicts quite accurately how MPTP destroys dopaminergic neurons of the substantia nigra.

External links

"Surprising Clue to Parkinson's". Time Magazine. 24 June 2001.
"About the Parkinson Institute". The Parkinson Institute.
"How a Junkie's Brain Helps Parkinson's Patients". Wired. 21 September 2007.
Erowid MPTP Vault - Contains information regarding MPTP as a neurotoxin

References

^ ^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. Parkinson's Disease. Diagnosis and Clinical Management. Demos Medical Publishing.
^ "PARKINSON’S DISEASE MODELS". 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.
^ Fahn, S. (1996). "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". The New England Journal of Medicine 335 (26): 2002–2003. doi:10.1056/NEJM199612263352618.
^ "Success reported using fetal tissue to repair a brain". The New York Times. 26 November 1992.
^ Langston, J. W.; Palfreman, J. (May 1995). The Case of the Frozen Addicts. Pantheon Books. ISBN 0-679-42465-2.
^ Jackson-Lewis, V.; Przedborski, S. (2007). "Protocol for the MPTP Mouse Model of Parkinson's Disease". Nature Protocols 2 (1): 141–151. doi:10.1038/nprot.2006.342. PMID 17401348.
^ "Pesticides and Parkinson's Disease - A Critical Review" (pdf). Institute of Environment and Health, Cranfield University. October 2005. ^{[dead link]}
^ "Summary of the Article by Dr. Greenamyre on Pesticides and Parkinson's Disease". National Institute of Neurological Disorders and Stroke. 9 February 2005. ^{[dead link]}
^ Lee, J.; Ziering, A.; Heineman, S. D.; Berger, L. (1947). "Piperidine Derivatives. Part II. 2-Phenyl- and 2-Phenylalkyl-Piperidines". Journal of Organic Chemistry 12 (6): 885–893. doi:10.1021/jo01170a021.
^ ^a ^b Vinken, P. J.; Bruyn, G. W. (1994). Intoxications of the Nervous System. Elsevier Health Sciences. p. 369. ISBN 0-444-81284-9.

UpToDate Contents

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1. Etiology and pathogenesis of Parkinson disease
2. 小児および思春期における類似麻薬の乱用 designer drugs of abuse
3. 虚血プレコンディショニングの定義および病因 definition and pathogenesis of ischemic preconditioning
4. パーキンソン病の診断 diagnosis of parkinson disease
5. 小児および思春期におけるオピオイド中毒 opioid intoxication in children and adolescents

English Journal

Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons.

Wang J, Song N, Jiang H, Wang J, Xie J.SourceDepartment of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China.
Biochimica et biophysica acta.Biochim Biophys Acta.2013 May;1832(5):618-25. doi: 10.1016/j.bbadis.2013.01.021. Epub 2013 Jan 31.
Both inflammatory processes associated with microglia activation and abnormal iron deposit in dopaminergic neurons are involved in the pathogenesis of Parkinson's disease (PD). However, the relationship between neuroinflammation and iron accumulation was not fully elucidated. In the present study, w
PMID 23376588

Adenosine monophosphate-activated protein kinase overactivation leads to accumulation of α-synuclein oligomers and decrease of neurites.

Jiang P, Gan M, Ebrahim AS, Castanedes-Casey M, Dickson DW, Yen SH.SourceDepartment of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Neurobiology of aging.Neurobiol Aging.2013 May;34(5):1504-15. doi: 10.1016/j.neurobiolaging.2012.11.001. Epub 2012 Nov 28.
Neuronal inclusions of α-synuclein (α-syn), termed Lewy bodies, are a hallmark of Parkinson disease (PD). Increased α-syn levels can occur in brains of aging human and neurotoxin-treated mice. Because previous studies have shown increased brain lactate levels in aging brains, in PD affected subje
PMID 23200460

Estrogen receptors and lesion-induced response of striatal dopamine receptors.

Al Sweidi S, Morissette M, Rouillard C, Di Paolo T.SourceFaculty of Pharmacy, Laval University, Quebec City, QC, Canada G1K 7P4; Neuroscience unit, Centre de recherche du CHU de Québec, Quebec City, QC, Canada G1V 4G2.
Neuroscience.Neuroscience.2013 Apr 16;236:99-109. doi: 10.1016/j.neuroscience.2012.12.058. Epub 2013 Jan 26.
Neuroprotection by 17β-estradiol and an estrogen receptor (ER) agonist against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion were shown to implicate protein kinase B (Akt) signaling in mice. In order to evaluate the associated mechanisms, this study compared estrogen receptor alpha (ER
PMID 23357113

Japanese Journal

The effect of Ndrg2 expression on astroglial activation

Takeichi Toshiaki,Takarada-Iemata Mika,Hashida Koji,Sudo Hirofumi,Okuda Tomohiko,Kokame Koichi,Hatano Taku,Takanashi Masashi,Funabe Sayaka,Hattori Nobutaka,Kitamura Osamu,Kitao Yasuko,Hori Osamu
Neurochemistry International 59(1), 21-27, 2011-08
… To study the expression and possible role of Ndrg2 in quiescent and activated astrocytes, mice were administrated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP), a Parkinson disease (PD)-related neurotoxin which causes both neurodegeneration and glial activation. …
NAID 120003221535

Neuroprotective Effect of Kaempferol against a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Mouse Model of Parkinsons Disease

Li Shen,Pu Xiao-Ping
Biological & Pharmaceutical Bulletin 34(8), 1291-1296, 2011
… In the present study, we investigated the neuroprotective effects of kaempferol in the mouse model of Parkinsons disease, which was induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). … We confirmed that MPTP led to behavioral deficits, depletion of dopamine and its metabolites, reduction in superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity, and the elevation of malondialdehyde (MDA) levels in the substantia nigra. …
NAID 130000936601

Related Pictures

★リンクテーブル★

リンク元	「メチルフェニルテトラヒドロピリジン」「黒質緻密部」「1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine」
拡張検索	「MPTP誘発実験的パーキンソニズム」「MPTP-induced experimental parkinsonism」「MPTP中毒」「MPTP誘発パーキンソニズム」「MPTP poisoning」
関連記事	「MP」

「メチルフェニルテトラヒドロピリジン」

MPTP
	IUPAC name 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Identifiers
CAS number	28289-54-5
PubChem	1388
ChemSpider	1346
EC number	248-939-7
KEGG	C04599
MeSH	1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
ChEBI	CHEBI:17963
ChEMBL	CHEMBL24172
IUPHAR ligand	280
Jmol-3D images	Image 1
	SMILES c2c(/C1=C/CN(C)CC1)cccc2 ;
	InChI InChI=1S/C12H15N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-7H,8-10H2,1H3 ; Key: PLRACCBDVIHHLZ-UHFFFAOYSA-N InChI=1/C12H15N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-7H,8-10H2,1H3; Key: PLRACCBDVIHHLZ-UHFFFAOYAV ;
Properties
Molecular formula	C12H15N
Molar mass	173.25 g/mol
Melting point	39 °C, 312 K, 102 °F
Boiling point	130 °C, 403 K, 266 °F
Solubility in water	slightly soluble
Hazards
NFPA 704	0 4 0
	(verify) (what is: /?); Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
	Infobox references