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Molecular Pharmacology

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Research ArticleArticle

The Selective Toxicity of 1-Methyl-4-phenylpyridinium to Dopaminergic Neurons: The Role of Mitochondrial Complex I and Reactive Oxygen Species Revisited

Ken Nakamura, Vytautas P. Bindokas, Jeremy D. Marks, David A. Wright, David M. Frim, Richard J. Miller and Un Jung Kang
Molecular Pharmacology August 2000, 58 (2) 271-278; DOI: https://doi.org/10.1124/mol.58.2.271
Ken Nakamura
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Vytautas P. Bindokas
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Jeremy D. Marks
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David A. Wright
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David M. Frim
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Richard J. Miller
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Un Jung Kang
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Abstract

1-Methyl-4-phenylpyridinium (MPP+) is selectively toxic to dopaminergic neurons and has been studied extensively as an etiologic model of Parkinson's disease (PD) because mitochondrial dysfunction is implicated in both MPP+ toxicity and the pathogenesis of PD. MPP+ can inhibit mitochondrial complex I activity, and its toxicity has been attributed to the subsequent mitochondrial depolarization and generation of reactive oxygen species. However, MPP+ toxicity has also been noted to be greater than predicted by its effect on complex I inhibition or reactive oxygen species generation. Therefore, we examined the effects of MPP+ on survival, mitochondrial membrane potential (ΔΨm), and superoxide and reduced glutathione levels in individual dopaminergic and nondopaminergic mesencephalic neurons. MPP+ (5 μM) selectively induced death in fetal rat dopaminergic neurons and caused a small decrease in their ΔΨm. In contrast, the specific complex I inhibitor rotenone, at a dose (20 nM) that was less toxic than MPP+ to dopaminergic neurons, depolarized ΔΨm to a greater extent than MPP+. In addition, neither rotenone nor MPP+ increased superoxide in dopaminergic neurons, and MPP+ failed to alter levels of reduced glutathione. Therefore, we conclude that increased superoxide and loss of ΔΨm may not represent primary events in MPP+ toxicity, and complex I inhibition alone is not sufficient to explain the selective toxicity of MPP+ to dopaminergic neurons. Clarifying the effects of MPP+ on energy metabolism may provide insight into the mechanism of dopaminergic neuronal degeneration in PD.

Footnotes

    • Received September 21, 1999.
    • Accepted May 4, 2000.
  • Send reprint requests to: Un Jung Kang, M.D., MC 2030, S225B, Department of Neurology, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637. E-mail:u-kang{at}uchicago.edu

  • This research was supported by the Brain Research Foundation, Louis R. Block Fund, National Parkinson Foundation, Parkinson Disease Foundation, United Parkinson Foundation, and U.S. Public Health Service Grant NS07113.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (2)
Molecular Pharmacology
Vol. 58, Issue 2
1 Aug 2000
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Research ArticleArticle

The Selective Toxicity of 1-Methyl-4-phenylpyridinium to Dopaminergic Neurons: The Role of Mitochondrial Complex I and Reactive Oxygen Species Revisited

Ken Nakamura, Vytautas P. Bindokas, Jeremy D. Marks, David A. Wright, David M. Frim, Richard J. Miller and Un Jung Kang
Molecular Pharmacology August 1, 2000, 58 (2) 271-278; DOI: https://doi.org/10.1124/mol.58.2.271

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Research ArticleArticle

The Selective Toxicity of 1-Methyl-4-phenylpyridinium to Dopaminergic Neurons: The Role of Mitochondrial Complex I and Reactive Oxygen Species Revisited

Ken Nakamura, Vytautas P. Bindokas, Jeremy D. Marks, David A. Wright, David M. Frim, Richard J. Miller and Un Jung Kang
Molecular Pharmacology August 1, 2000, 58 (2) 271-278; DOI: https://doi.org/10.1124/mol.58.2.271
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