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N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1−/− mouse

Authors

  • Ari E. Berman Ph.D.,

    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
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    • Ari E. Berman and Wai Yee Chan contributed equally to this work.

  • Wai Yee Chan Ph.D.,

    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
    Current affiliation:
    1. Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Princeton, NJ 08534
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    • Ari E. Berman and Wai Yee Chan contributed equally to this work.

  • Angela M. Brennan Ph.D.,

    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
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  • Reno C. Reyes Ph.D.,

    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
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  • Brittany L. Adler B.S.,

    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
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  • Sang Won Suh Ph.D.,

    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
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  • Tiina M. Kauppinen Ph.D.,

    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
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  • Ylva Edling Ph.D.,

    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
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  • Raymond A. Swanson M.D.

    Corresponding author
    1. Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA
    • Neurology VAMC, 4150 Clement St., San Francisco, CA 94121
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Abstract

Objective

Dopaminergic neuronal death in Parkinson's disease (PD) is accompanied by oxidative stress and preceded by glutathione depletion. The development of disease-modifying therapies for PD has been hindered by a paucity of animal models that mimic these features and demonstrate an age-related progression. The EAAC1−/− mouse may be useful in this regard, because EAAC1−/− mouse neurons have impaired neuronal cysteine uptake, resulting in reduced neuronal glutathione content and chronic oxidative stress. Here we aimed to (1) characterize the age-related changes in nigral dopaminergic neurons in the EAAC1−/− mouse, and (2) use the EAAC1−/− mouse to evaluate N-acetylcysteine, a membrane-permeable cysteine pro-drug, as a potential disease-modifying intervention for PD.

Methods

Wild-type mice, EAAC1−/− mice, and EAAC1−/− mice chronically treated with N-acetylcysteine were evaluated at serial time points for evidence of oxidative stress, dopaminergic cell death, and motor abnormalities.

Results

EAAC1−/− mice showed age-dependent loss of dopaminergic neurons in the substantia nigra pars compacta, with more than 40% of these neurons lost by age 12 months. This neuronal loss was accompanied by increased nitrotyrosine formation, nitrosylated α-synuclein, and microglial activation. These changes were substantially reduced in mice that received N-acetylcysteine.

Interpretation

These findings suggest that the EAAC1−/− mouse may be a useful model of the chronic neuronal oxidative stress that occurs in PD. The salutary effects of N-acetylcysteine in this mouse model provide an impetus for clinical evaluation of glutathione repletion in PD. ANN NEUROL 2010

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