Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: Implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity

Heikkila, Richard E.; Nicklas, William J.; Vyas, I; Duvoisin, Roger C.

doi:10.1016/0304-3940(85)90580-4

Cited by 270 publications

(116 citation statements)

References 13 publications

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“…Because rotenone is poorly absorbed by the gastrointestinal (GI) tract, the initial studies using rotenone treatment in rats utilized stereotaxic infusion of the toxin into the parenchyma (45). While robust decreases in striatal dopamine and serotonin levels were observed, these early versions of the rat rotenone model involved high concentrations of rotenone and were not very specific for dopamine neurons and terminals.…”

Section: Rotenone Models Of Parkinsonismmentioning

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: Rotenone Models Of Parkinsonismmentioning

confidence: 99%

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Martinez

Greenamyre

2012

Antioxidants & Redox Signaling

222

155

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“…MPTP can selectively inhibit mitochondrial complex I activity [81,82]. Since this discovery the role of complex I in PD has been intensely studied.…”

Section: Mitochondrial Complex Imentioning

confidence: 99%

Oxidative and nitrative protein modifications in Parkinson's disease

Danielson

Andersen

2008

Free Radical Biology and Medicine

184

121

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Parkinson's disease (PD) is a complex neurodegenerative syndrome likely involving contributions from various factors in individuals including genetic susceptibility, exposure to environmental toxins, and the aging process itself. Increased oxidative stress appears to be a common causative aspect involved in the preferential loss of dopaminergic neurons in a region of the brain prominently affected by the disorder, the substantia nigra (SN). Loss of dopaminergic SN neurons is responsible for the classic clinical motor symptoms associated with PD. Several oxidative and nitrative posttranslational modifications (PTMs) have been identified on proteins pertinent to PD that may affect this or other aspects of disease progression. In this review, we discuss several examples of such PTMs to illustrate their potential consequences in terms of initiation or progression of PD neuropathophysiology.

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“…Moreover, the nigrostriatal dopaminergic neurons are selectively destroyed in mouse (Heikkila et al, 1984), monkey (Langston et al, 1984), and human following the systemic administration of I-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), an inhibitor of the complex I of the respiratory chain, which is less toxic toward the other catecholaminergic neurons in spite of their ability to accumulate it. Similarly, the local injection of rotenone, an inhibitor of the complex I of the respiratory chain, into the median forebrain bundle greatly diminished the striatal content of dopamine without affecting that of GABA (Heikkila et al, 1985). This latter result suggests that rotenone is more toxic for the nigrostriatal dopaminergic neurons than for the striatonigral GABAergic neurons.…”

mentioning

confidence: 92%

A selective toxicity toward cultured mesencephalic dopaminergic neurons is induced by the synergistic effects of energetic metabolism impairment and NMDA receptor activation

1995

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Numerous observations strongly support the hypothesis that dopaminergic neurons could be particularly vulnerable to an impairment of their energetic metabolism. In order to demonstrate the existence of such a selective vulnerability, the toxic effects of rotenone, an inhibitor of complex I of the respiratory chain, and of glutamate, which is very likely involved in the neurotoxicity induced by an energetic stress, were analyzed on cultured mouse mesencephalic neurons. Toxicity toward dopaminergic and GABAergic neurons was compared by measuring the residual uptakes of dopamine and GABA. Exposure to 5 nM rotenone for 6 hr or to a low concentration of glutamate (100 microM) for 1 hr did not lead to a high selective toxic effect on dopaminergic neurons. In contrast, dopaminergic neurons were three times less resistant to the sequential exposure to rotenone and glutamate than GABAergic neurons. A particular resistance of mesencephalic GABAergic neurons to the synergistic toxic effects of rotenone and glutamate was ruled out since two other neuronal types, the striatal cholinergic and GABAergic neurons, displayed the same weak vulnerability as the mesencephalic GABAergic neurons. This selective toxic effect of glutamate on rotenone- pretreated dopaminergic neurons was blocked by either AMPA or NMDA receptor antagonists and mimicked by combined treatment with AMPA and NMDA, or by NMDA alone when the medium was deprived of Mg2+ ions. Moreover, this NMDA-selective neurotoxicity was critically dependent on the presence of a physiological extracellular sodium concentration, since the use of choline chloride instead of sodium chloride had a protective effect on dopaminergic neurons.

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Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: Implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity

Cited by 270 publications

References 13 publications

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Oxidative and nitrative protein modifications in Parkinson's disease

A selective toxicity toward cultured mesencephalic dopaminergic neurons is induced by the synergistic effects of energetic metabolism impairment and NMDA receptor activation

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