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Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease

Nature Medicine volume 5, pages 1403–1409 (1999)Cite this article

Abstract

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease. Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.

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Figure 1: MPTP-induced glial reaction.
Figure 2: MPTP-induced iNOS upregulation.
Figure 3: MPTP-induced neuronal loss and microglial reaction in iNOS–/– mice.

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Acknowledgements

We thank V.H. Perry and J. Goldman for their advice on the glial studies; H. Ischiropoulos for his guidance on the nitrotyrosine studies; and N. Romero and D. Guestella for their assistance in maintaining and genotyping the iNOS mutant mice. This study was supported by National Institute of Neurological Disorders and Stroke grant R29 NS37345, RO1 NS38586 and P50 NS38370, and US Department of Defense contract number DAMD 17-99-1-9474 (S.P.); the Lowenstein Foundation and the Parkinson's Disease Foundation (G.L., V.J-L., S.P.); National Institutes of Health/National Institute of Neurological Disorders and Stroke grant P50 NS38377; the Mitchell Family foundation (A.S.M, V.L.D, T.M.D); Public Health Service/Career Investigator Development Award grant NS 1K08N2035; and the American Parkinson Disease Association (A.S.M). M.V. is recipient of a fellowship from the Human Frontier Science Program Organization, and S.P. is recipient of the Cotzias Award from the American Parkinson Disease Association.

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Authors and Affiliations

  1. Department of Neurology, Columbia University, New York, 10032, New York, USA

    Gabriel T. Liberatore, Vernice Jackson-Lewis, Slobodanka Vukosavic, Miquel Vila & Serge Przedborski

  2. Department of Pathology, Columbia University, New York, 10032, New York, USA

    Serge Przedborski

  3. Departments of Neurology, Neuroscience and Physiology Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Allen S. Mandir, Valina L. Dawson & Ted M. Dawson

  4. Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, 08854, New Jersey, USA

    W. Geoffrey McAuliffe

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Correspondence to Serge Przedborski.

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Liberatore, G., Jackson-Lewis, V., Vukosavic, S. et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5, 1403–1409 (1999). https://doi.org/10.1038/70978

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