Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism

Abstract

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces an irreversible neurological syndrome in man1,2 and monkey3 which is similar to idiopathic Parkinson's disease in its clinical, pathological, neurochemical and pharmacological response properties. MPTP is selectively neurotoxic to the dopaminergic regions of the brain, destroying neurones in the substantia nigra (A8 and A9 cells, nigrostriatal system) but not the ventral tegmental area (A10 cells, mesolimbic system)3. Selective dopamine depletion and nigral cell loss after MPTP treatment has also been reported recently in the mouse4. The mechanism by which a peripherally administered, low-molecular weight compound exerts permanent but selective toxic effects on dopamine systems in the brain may be relevant to parkinsonian syndromes induced by other toxins and to the disease process in idiopathic Parkinson's disease. We report here that MPTP is oxidized in the brain to a pyridinium species (a compound with potent herbicidal activity) and, in the monkey, is trapped intraneuronally. Furthermore, we demonstrate that this enzymatic oxidation is blocked in vivo in the mouse by a monoamine oxidase inhibitor, a condition which also blocks the neurotoxicity5, indicating that the oxidative metabolism of MPTP is required for its neurotoxic effect.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Davis, G. C. et al. Psychiat. Res. 1, 249–254 (1979).

    Article  ADS  CAS  Google Scholar 

  2. Langston, J. W., Ballard, P., Tetrud, J. W. & Irwin, I. Science 219, 979–980 (1983).

    Article  ADS  CAS  Google Scholar 

  3. Burns, R. S. et al. Proc. natn. Acad. Sci. U.S.A. 80, 4546–4550 (1983).

    Article  ADS  CAS  Google Scholar 

  4. Heikkila, R. E., Hess, A. & Duvoisin, R. C. Science 224, 1451–1453 (1984).

    Article  ADS  CAS  Google Scholar 

  5. Heikkila, R. E., Manzino, L., Cabbat, F. S. & Duvoisin, R. C. Nature 311, 467–469 (1984).

    Article  ADS  CAS  Google Scholar 

  6. Lyle, R. E., Nelson, D. A. & Anderson, P. S. Tetrahedron Lett. 553–557 (1962).

  7. Ward, D. P. et al. Drug Metab. Disposit. 10, 690–695 (1982).

    CAS  Google Scholar 

  8. Bodor, N., Farag, H. H. & Brewster, M. E. III Science 214, 1370–1372 (1981).

    Article  ADS  CAS  Google Scholar 

  9. Jacobowitz, D. M., Burns, R. S., Chiueh, C. C. & Kopin, I. J. Psychopharmac. Bull. 20, 416–422 (1984).

    CAS  Google Scholar 

  10. Swartzbek, R. A. Proc. 12th Br. Weed Control Conf. Vol. 2, 851–856 (1974).

    Google Scholar 

  11. Cohen, G. Neurotoxicology 5, 77–82 (1984).

    CAS  PubMed  Google Scholar 

  12. Birkmeyer, W., Knoll, J., Riederer, P. & Youdim, M. B. H. Mod. Probl. Pharmacopsychiat. 19, 170–176 (1983).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Markey, S., Johannessen, J., Chiueh, C. et al. Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311, 464–467 (1984). https://doi.org/10.1038/311464a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/311464a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing