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

  1. Ken Nakamura1,
  2. Vytautas P. Bindokas3,
  3. Jeremy D. Marks4,
  4. David A. Wright2,
  5. David M. Frim4,5,
  6. Richard J. Miller1,3 and
  7. Un Jung Kang1,2,3
  1. 1Committee on Neurobiology (K.N., R.J.M., U.J.K.), Departments of2Neurology (D.A.W., U.J.K.), 3Neurobiology, Pharmacology & Physiology (V.P.B., R.J.M., U.J.K.), 4Pediatrics (J.D.M., D.M.F.), and5Surgery (D.M.F.), The University of Chicago, Chicago, Illinois

    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

    • 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.

    • Abbreviations:
      PD
      Parkinson's disease
      MPP+
      1-methyl-4-phenylpyridinium
      ΔΨm
      mitochondrial membrane potential
      GSH
      reduced glutathione
      MPTP
      1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      NO
      nitric oxide
      SOD
      superoxide dismutase
      DAB
      3,3′-diaminobenzidine tetrahydrochloride
      DMEM
      Dulbecco's modified Eagle's medium
      DMSO
      dimethyl sulfoxide
      NFP
      neurofilament protein 200
      TH
      tyrosine hydroxylase
      JC-1
      5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide
      HEt
      hydroethidine
      Et
      ethidium
      MCB
      monochlorobimane
      BSO
      l-buthionine-[S,R]sulfoximine
      FCCP
      carbonyl cyanidep-trifluoromethoxy-phenylhydrazone
      DIC
      differential interference contrast
      ROS
      reactive oxygen species
      Cu/Zn-SOD
      copper/zinc form of SOD
      • Received September 21, 1999.
      • Accepted May 4, 2000.
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    1. Molecular Pharmacology August 1, 2000 vol. 58 no. 2 271-278
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