1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and free radicals in vitro

Zl, Rossetti; Sotgiu, A.; De, Sharp; Hadjiconstantinou, Maria; Nh, Neff

doi:10.1016/0006-2952(88)90674-0

Cited by 125 publications

(46 citation statements)

References 15 publications

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“…Once inside the neuron and during the acute phase of MPTP-induced death, there are a few routes that MPP + can take: it can enter the vesicular pathway, bind to vesicular monoamine transporters and translocate into synaptosomal vesicles (61), it can remain in the cytosol and interact with various cytosolic enzymes (53), or it can be concentrated within mitochondria via a mechanism dependent on mitochondrial transmembrane potential (80,84). Within the mitochondria, MPP + binds to complex 1, uncoupling the oxidation of NADH-linked substrates and consequently disrupting the flow of electrons along the ETC, resulting in decreased ATP production and increased generation of ROS (72).…”

Section: Mptp Metabolism and Mitochondrial Mechanisms Of Neurotoxicitymentioning

confidence: 99%

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Martinez

Greenamyre

2012

Antioxidants & Redox Signaling

222

155

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Significance: Parkinson's disease (PD) is a neurodegenerative disorder characterized, in part, by the progressive and selective loss of dopaminergic neuron cell bodies within the substantia nigra pars compacta (SNpc) and the associated deficiency of the neurotransmitter dopamine (DA) in the striatum, which gives rise to the typical motor symptoms of PD. The mechanisms that contribute to the induction and progressive cell death of dopaminergic neurons in PD are multi-faceted and remain incompletely understood. Data from epidemiological studies in humans and molecular studies in genetic, as well as toxin-induced animal models of parkinsonism, indicate that mitochondrial dysfunction occurs early in the pathogenesis of both familial and idiopathic PD. In this review, we provide an overview of toxin models of mitochondrial dysfunction in experimental Parkinson's disease and discuss mitochondrial mechanisms of neurotoxicity. Recent Advances: A new toxin model using the mitochondrial toxin trichloroethylene was recently described and novel methods, such as intranasal exposure to toxins, have been explored. Additionally, recent research conducted in toxin models of parkinsonism provides an emerging emphasis on extranigral aspects of PD pathology. Critical Issues: Unfortunately, none of the existing animal models of experimental PD completely mimics the etiology, progression, and pathology of human PD. Future Directions: Continued efforts to optimize established animal models of parkinsonism, as well as the development and characterization of new animal models are essential, as there still remains a disconnect in terms of translating mechanistic observations in animal models of experimental PD into bona fide diseasemodifying therapeutics for human PD patients. Antioxid. Redox Signal. 16, 920-934.

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Section: Mptp Metabolism and Mitochondrial Mechanisms Of Neurotoxicitymentioning

confidence: 99%

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Martinez

Greenamyre

2012

Antioxidants & Redox Signaling

222

155

View full text Add to dashboard Cite

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“…Within the dopaminergic neurons, MPP ϩ sequesters inside the mitochondrial compartment because of the positive charge it carries (8) and preferentially binds to and inhibits complex I of the electron transport chain (9). Inhibition of complex I leading to lower ATP generation (10), increased production of reactive oxygen species (ROS) (11,12), and eventual cell death are believed to be the steps leading to Parkinson disease (13).…”

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confidence: 99%

Metabolism of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine by Mitochondrion-targeted Cytochrome P450 2D6

Bajpai

Sangar

Singh

et al. 2013

Journal of Biological Chemistry

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“…The discovery that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can selectively destroy the doparninergic cells in the SN to cause a parkinsonian syndrome in humans and primates {C-S} has prompted the search for other environmental toxins. MPTP, via its metabolites MPDP+ and MPP+, can generate free radicals [9], although an effect of MPP+ on complex I …”

mentioning

confidence: 99%

Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia

et al. 1992

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Previously we have shown that cell death in the substantia nigra (SN) in Parkinson's disease (PD) is associated with an increase in iron content but a decrease in the level of the iron-binding protein ferritin. Alterations in other metal ion levels were also observed; copper levels were reduced, whereas zinc levels were increased. The importance of these changes in iron, ferritin, and other metal ions in the pathophysiology of PD depends on whether they are specific to the illness. We measured levels of iron, copper, zinc, manganese, and ferritin in postmortem tissue from patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (which shows pathology in the SN and striatum) and Huntington's disease (HD) (which shows pathological changes in the striatum, compared with control subjects). Total iron levels were elevated in areas of the basal ganglia showing pathological changes in these disorders. In particular, total iron content was increased in SN in PD, PSP, and MSA, but not in HD. Total iron levels in the striatum (caudate nucleus and/or putamen) were increased in PSP, MSA, and HD, but not in PD. There were no consistent alterations in manganese levels in the basal ganglia in any of the diseases studied. Copper levels were decreased in the SN in PD and in the cerebellum in PSP, and were elevated in the putamen and possibly the SN in HD. Zinc levels were only increased in PD in the SN, the caudate nucleus, and the putamen.(ABSTRACT TRUNCATED AT 250 WORDS)

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and free radicals in vitro

Cited by 125 publications

References 15 publications

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Metabolism of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine by Mitochondrion-targeted Cytochrome P450 2D6

Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia

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