関: MPTP

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the univalent radical CH3- derived from methane (同)methyl_group, methyl radical

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/05/15 23:56:23」(JST)

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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,^[3] however most of the recent studies indicate that MPTP can result in Parkinsonism-like syndromes in mice (especially chronic syndromes).^[4]^[5] It is believed that the lower levels of MAO-B in the rodent brain's capillaries may be responsible for this.^[3]

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 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.^[6]

In 1982, six 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.^[7]

Langston documented the case in his 1995 book The Case of the Frozen Addicts, which was later featured in two NOVA productions by PBS.^[8]

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.^[9]

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.^[10]

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.^[11]

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.^[12] 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.^[13]

MPTP is used in industry as a chemical intermediate; the chloride of the toxic metabolite MPP+ was turned into the herbicide cyperquat.^[13]

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.
MPTP-induced Parkinson's is featured in the Law & Order episode "Stiff."

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

^ "1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine". ChemIDplus.
^ Buchi, I. J. (1952). Helvetica Chimica Acta 35: 1527–1536.
^ ^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. Cite uses deprecated parameters (help)
^ 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. パーキンソン病の病因および発症機序 etiology and pathogenesis of parkinson disease
2. Diagnosis and differential diagnosis of Parkinson disease
3. 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
4. Myocardial ischemic conditioning: Pathogenesis

English Journal

Treadmill exercise reverses dendritic spine loss in direct and indirect striatal medium spiny neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease.

Toy WA1, Petzinger GM2, Leyshon BJ3, Akopian GK4, Walsh JP4, Hoffman MV3, Vučković MG3, Jakowec MW2.Author information 1The George and MaryLou Boone Center for Parkinson's Disease Research, Department of Neurology, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: wtoy@usc.edu.2The George and MaryLou Boone Center for Parkinson's Disease Research, Department of Neurology, University of Southern California, Los Angeles, CA 90033, USA; The George and MaryLou Boone Center for Parkinson's Disease Research, Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA 90033, USA.3The George and MaryLou Boone Center for Parkinson's Disease Research, Department of Neurology, University of Southern California, Los Angeles, CA 90033, USA.4The George and MaryLou Boone Center for Parkinson's Disease Research, Andrus Center for Gerontology, University of Southern California, Los Angeles, CA 90033, USA.AbstractExercise has been shown to be beneficial for Parkinson's disease (PD). A major interest in our lab has been to investigate how exercise modulates basal ganglia function and modifies disease progression. Dopamine (DA) depletion leads to loss of dendritic spines within the caudate nucleus and putamen (striatum) in PD and its animal models and contributes to motor impairments. Striatal medium spiny neurons (MSNs) can be delineated into two populations, the dopamine D1 receptor (DA-D1R)-containing MSNs of the direct pathway and dopamine D2 receptor (DA-D2R)-containing MSNs of the indirect pathway. There is evidence to suggest that the DA-D2R-indirect pathway MSNs may be preferentially affected after DA-depletion with a predominate loss of dendritic spine density when compared to MSNs of the DA-D1R-direct pathway in rodents; however, others have reported that both pathways may be affected in primates. The purpose of this study was to investigate the effects of intensive exercise on dendritic spine density and arborization in MSNs of these two pathways in the MPTP mouse model of PD. We found that MPTP led to a decrease in dendritic spine density in both DA-D1R- and DA-D2R-containing MSNs and 30days of intensive treadmill exercise led to increased dendritic spine density and arborization in MSNs of both pathways. In addition, exercise increased the expression of synaptic proteins PSD-95 and synaptophysin. Taken together these findings support the potential effect of exercise in modifying synaptic connectivity within the DA-depleted striatum and in modifying disease progression in individuals with PD.
Neurobiology of disease.Neurobiol Dis.2014 Mar;63:201-9. doi: 10.1016/j.nbd.2013.11.017. Epub 2013 Dec 5.
Exercise has been shown to be beneficial for Parkinson's disease (PD). A major interest in our lab has been to investigate how exercise modulates basal ganglia function and modifies disease progression. Dopamine (DA) depletion leads to loss of dendritic spines within the caudate nucleus and putamen
PMID 24316165

D1 receptor agonist improves sleep-wake parameters in experimental parkinsonism.

Hyacinthe C1, Barraud Q2, Tison F3, Bezard E4, Ghorayeb I5.Author information 1Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. Electronic address: carole.hyacinthe@u-bordeaux2.fr.2Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. Electronic address: quentin.barraud@epfl.ch.3Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; Service de Neurologie, CHU de Bordeaux Haut-Lévêque, Pessac, France. Electronic address: francois.tison@chu-bordeaux.fr.4Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China. Electronic address: erwan.bezard@u-bordeaux2.fr.5Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; Département de Neurophysiologie Clinique, CHU de Bordeaux Pellegrin, Bordeaux, France. Electronic address: imad.ghorayeb@u-bordeaux2.fr.AbstractBoth excessive daytime sleepiness (EDS) and rapid eye movement (REM) sleep deregulation are part of Parkinson's disease (PD) non-motor symptoms and may complicate dopamine replacement therapy. We report here that dopamine agonists act differentially on sleep architecture in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque monkey. Continuous sleep and wake electroencephalographic monitoring revealed no effect of the selective dopamine D2 receptor agonist quinpirole on EDS, whereas the selective dopamine D1 receptor agonist SKF38393 efficiently alleviated EDS and restored REM sleep to baseline values. The present results question the relevance of abandoning D1 receptor agonist treatment in PD as it might actually improve sleep-related disorders.
Neurobiology of disease.Neurobiol Dis.2014 Mar;63:20-4. doi: 10.1016/j.nbd.2013.10.029. Epub 2013 Nov 6.
Both excessive daytime sleepiness (EDS) and rapid eye movement (REM) sleep deregulation are part of Parkinson's disease (PD) non-motor symptoms and may complicate dopamine replacement therapy. We report here that dopamine agonists act differentially on sleep architecture in the 1-methyl-4-phenyl-1,2
PMID 24211719

Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice.

Yabuki Y1, Ohizumi Y2, Yokosuka A3, Mimaki Y3, Fukunaga K4.Author information 1Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.2School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Department of Anti-dementia Functional Food Development, Graduate School of Engineering, Tohoku University, Sendai, Japan; Laboratory of Kampo Medicines, Yokohama College of Pharmacy, Yokohama, Japan; Kasei Fukushi Research Center, Tohoku Fukushi University, Sendai, Japan.3Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.4Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp.AbstractNobiletin, a polymethoxylated flavonoid found in citrus fruit peel, reportedly improves memory impairment in rodent models. Here we report its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor and cognitive deficits. Nobiletin administration (50mg/kg i.p.) for 2 consecutive weeks improved motor deficits seen in MPTP-induced Parkinson model mice by 2weeks, an effect that continued until 2weeks after drug withdrawal. Drug treatment promoted similar rescue of MPTP-induced cognitive impairment at equivalent time points. Nonetheless, nobiletin treatment did not block loss of dopaminergic neurons seen in the MPTP-treated mouse midbrain, nor did it rescue decreased tyrosine hydroxylase (TH) protein levels seen in the striatum or hippocampal CA1 region of these mice. Interestingly, nobiletin administration (50mg/kg i.p.) rescued reduced levels of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation at Thr-34 of dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) in striatum and hippocampal CA1 to levels seen in sham-operated mice. Likewise, CaMKII- and cAMP kinase-dependent TH phosphorylation was significantly restored by nobiletin treatment. MPTP-induced reduction of dopamine contents in the striatum and hippocampal CA1 region was improved by nobiletin administration (50mg/kg i.p.). Acute intraperitoneal administration of nobiletin also enhanced dopamine release in striatum and hippocampal CA1, an effect partially inhibited by treatment with nifedipine (a L-type Ca(2+) channel inhibitor) or NNC 55-0396 (a T-type Ca(2+) channel inhibitor) and completely abolished by combined treatment with both. Overall, our study describes a novel nobiletin activity in brain and suggests that nobiletin rescues motor and cognitive dysfunction in MPTP-induced Parkinson model mice, in part by enhancing dopamine release.
Neuroscience.Neuroscience.2014 Feb 14;259:126-41. doi: 10.1016/j.neuroscience.2013.11.051. Epub 2013 Dec 4.
Nobiletin, a polymethoxylated flavonoid found in citrus fruit peel, reportedly improves memory impairment in rodent models. Here we report its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor and cognitive deficits. Nobiletin administration (50mg/kg i.p.) for 2 consecutive
PMID 24316474

Japanese Journal

Acacetin Protects Dopaminergic Cells against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Neuroinflammation in Vitro and in Vivo

Kim Hyo Geun,Ju Mi Sun,Ha Sang Keun [他]
Biological & pharmaceutical bulletin 35(8), 1287-1294, 2012-08
NAID 40019353630

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). …
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」「1-メチル-4-フェニル-1,2,3,6-テトラヒドロピリジン」
関連記事	「phenyl」「tetrahydropyridine」

「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−1
Melting point	40 °C (104 °F; 313 K)
Boiling point	128 to 132 °C (262 to 270 °F; 401 to 405 K) 12 Torr
Solubility in water	Slightly soluble
Hazards
NFPA 704	0 4 0
	Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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	Infobox references