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Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis

Nature Medicine volume 5, pages 347350 (1999) | Download Citation

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Abstract

Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations1,2. Mice with the G93A human SOD1 mutation have altered electron transport enzymes, and expression of the mutant enzyme in vitro results in a loss of mitochondrial membrane potential and elevated cytosolic calcium concentration3. Mitochondrial dysfunction may lead to ATP depletion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption4, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore5. We found that oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS.

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Acknowledgements

The secretarial assistance of S. Melanson is acknowledged. Photographic assistance was provided by S. Kuemmerle. This work was supported by NIH grant PO1 AG12292 (M.F.B. and R.J.F.), NS37102 (R.J.F.), the Veterans Administration (R.J.F.), the Muscular Dystrophy Association and the ALS Association, and NIMH grant MH11692 (A.M.K.).

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Affiliations

  1. Neurochemistry Laboratory, Neurology Service,Massachusetts General Hospital and Harvard Medical School, 32 Fruit Street, Boston, Massachusetts 02118, USA

    • Peter Klivenyi
    • , Russell T. Matthews
    • , Mikhail B. Bogdanov
    • , Ole A. Andreassen
    • , Gerald Mueller
    • , Marieke Wermer
    •  & M. Flint Beal
  2. Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts 02118, USA

    • Robert J. Ferrante
    •  & Autumn M. Klein
  3. Department of Veterans Affairs, 200 Spring Road, Bedford, Massachusetts 01730, USA

    • Robert J. Ferrante
    •  & Autumn M. Klein
  4. The Avicena Group, Inc., One Broadway, Suite 600, Cambridge, Massachusetts 02142, USA

    • Rima Kaddurah-Daouk
  5. Department of Neurology and Neuroscience, Cornell University Medical College, 525 East 68th Street, New York, New York 10021, USA

    • M. Flint Beal

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Correspondence to M. Flint Beal.

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https://doi.org/10.1038/6568