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Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington's disease

Authors

  • Ole A. Andreassen MD,

    1. Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston
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  • Robert J. Ferrante PhD,

    1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford
    2. Department of Neurology, Boston University School of Medicine, Boston, MA
    3. Department of Pathology, Boston University School of Medicine, Boston, MA
    4. Department of Psychiatry, Boston University School of Medicine, Boston, MA
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  • Hsueh-Meei Huang PhD,

    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY
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  • Alpaslan Dedeoglu PhD,

    1. Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston
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  • Larry Park PhD,

    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY
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  • Kimberly L. Ferrante BA,

    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY
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  • Jennifer Kwon BS,

    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY
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  • David R. Borchelt PhD,

    1. Department of Pathology, Johns Hopkins Medical School, Baltimore, MD
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  • Christopher A. Ross MD, PhD,

    1. Department of Pathology, Johns Hopkins Medical School, Baltimore, MD
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  • Gary E. Gibson PhD,

    1. Burke Medical Research Institute, White Plains, NY
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  • M. Flint Beal MD

    Corresponding author
    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY
    • Department of Neurology and Neuroscience, New York Presbyterian Hospital/Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021
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Abstract

Dichloroacetate (DCA) stimulates pyruvate dehydrogenase complex (PDHC) activity and lowers cerebral lactate concentrations. In the R6/2 and N171-82Q transgenic mouse models of Huntington's disease (HD), DCA significantly increased survival, improved motor function, delayed loss of body weight, attenuated the development of striatal neuron atrophy, and prevented diabetes. The percentage of PDHC in the active form was significantly reduced in R6/2 mice at 12 weeks of age, and DCA ameliorated the deficit. These results provide further evidence for a role of energy dysfunction in HD pathogenesis and suggest that DCA may exert therapeutic benefits in HD.

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