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


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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Figure 1: a and b, Effects of 1% or 2% creatine supplementation on survival in G93A transgenic mice.
Figure 2: Neuronal loss in the ventral horns of the lumbar spinal cord.
Figure 3: Effects of 1% creatine supplementation starting at 70 days of age on spinal cord 3-nitrotyrosine/tyrosine concentrations at 120 days of age.
Figure 4: Effect of 1% creatine supplementation on the conversion of 4HBA to 3,4DHBA in G93A transgenic mice after systemic administration of 3-NP.


  1. Wong, P.C. et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105–1116 (1995).

    Article  CAS  Google Scholar 

  2. Gurney, M.E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).

    Article  CAS  Google Scholar 

  3. Carri, M.T. et al. Expression of a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial alteration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH-SY5Y cells. FEBS Lett. 414, 365–368 (1997).

    Article  CAS  Google Scholar 

  4. Hemmer, W. & Wallimann, T. Functional aspects of creatine kinase in brain. Dev. Neurosci. 15, 249–260 (1993).

    Article  CAS  Google Scholar 

  5. O'Gorman, E., Beutner, G., Wallimann, T. & Brdiczka, D. Differential effects of creatine depletion on the regulation of enzyme activities and on creatine-stimulated mitochondrial respiration in skeletal muscle, heart, and brain. Biochim. Biophys. Acta 1276, 161–170 (1996).

    Article  Google Scholar 

  6. Gurney, M.E. et al. Antioxidants and inhibitors of glutamatergic transmission have therapeutic benefit in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol. 39, 147–157 (1996).

    Article  CAS  Google Scholar 

  7. Dugan, L.L. et al. Carboxyfullerenes as neuroprotective agents. Proc. Natl. Acad. Sci. USA 94, 9434–9439 (1997).

    Article  CAS  Google Scholar 

  8. Hottinger, A.F., Fine, E.G., Gurney, M.E., Zurn, A.D. & Aebischer, P. The copper chelator d-penicillamine delays onset of disease and extends survival in a transgenic moouse model of familial amyotrophic lateral sclerosis. Eur. J. Neurosci. 9, 1548–1551 (1997).

    Article  CAS  Google Scholar 

  9. Kostic, V. et al. Midbrain dopaminergic neuronal degeneration in a transgenic mouse model of familial amyotrophic lateral sclerosis. Ann. Neurol. 41, 497–504 (1997).

    Article  CAS  Google Scholar 

  10. Ferrante, R.J. et al. Increased 3-nitrotyrosine and oxidative damage in mice with a human Cu, Zn superoxide dismutase mutation. Ann. Neurol. 42, 326–334 (1997).

    Article  CAS  Google Scholar 

  11. Bogdanov, M.B., Ramos, L.E., Xu, X. & Beal, M.F. Elevated "hydroxyl radical" generation in vivo in an animal model of amyotrophic lateral sclerosis. J. Neurochem. 71, 1321–1324 (1998).

    Article  CAS  Google Scholar 

  12. Sasaki, S., Maruyama, S., Yamane, K., Sakuma, H. & Takeishi, M. Ultrastructure of swollen proximal axons of anterior horn neurons in motor neuron disease. J. Neurol. Sci. 97, 233–240 (1990).

    Article  CAS  Google Scholar 

  13. Siklos, L. et al. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann. Neurol. 39, 203–219 (1996).

    Article  CAS  Google Scholar 

  14. White, R.J. & Reynolds, I.J. Mitochondrial depolarization in glutamate-stimulated neurons: an early signal specific to excitotoxin exposure. J. Neurosci. 16, 5688–5697 (1996).

    Article  CAS  Google Scholar 

  15. O'Gorman, E. et al. The role of creatine kinase inhibition of mitochondrial permeability transition. FEBS Lett. 414, 253–257 (1997).

    Article  CAS  Google Scholar 

  16. Sauter, A. & Rudin, M. Determination of creatine kinase parameters in rat brain by NMR magnetization transfer: correlation with brain function. J. Biol. Chem. 268, 13166–13171 (1993).

    CAS  PubMed  Google Scholar 

  17. Corbett, R.J.T. & Laptook, A.R. Age-related changes in swine brain creatine kinase-catalyzed 31P exchange measured in vivo using 31P NMR magnetization transfer. J. Cereb. Blood Flow Metab. 14, 1070–1077 (1994).

    Article  CAS  Google Scholar 

  18. Xu, C.J. et al. Phosphocreatine-dependent glutamate uptake by synaptic vesicles. J. Biol. Chem. 271, 13435–13440 (1996).

    Article  CAS  Google Scholar 

  19. Rothstein, J.D., M., V.K., Levey, A.I., Martin, L. & Kuncl, R.W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38, 73–84 (1995).

    Article  CAS  Google Scholar 

  20. Sipila, I., Rapola, J., Simell, O. & Vannas, A. Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N. Engl. J. Med. 304, 867–870 (1981).

    Article  CAS  Google Scholar 

  21. Blanchard, V., Raisman-Vozari, R., Vyas, S., Michel, P.P., Javoy-Agid, F. & Uhl, G. Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of rat mesencephalon. Molec. Brain Res. 22, 29–40 (1994).

    Article  CAS  Google Scholar 

  22. Matthews, R.T. et al. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J. Neurosci. 18, 156–163 (1998).

    Article  CAS  Google Scholar 

  23. Bogdanov, M.B., Ramos, L.E., Xu, X. & Beal, M.F. Elevated "hydroxyl radical" generation in vivo in an animal model of amyotrophic lateral sclerosis. J. Neurochem. 71, 1321–1324 (1998).

    Article  CAS  Google Scholar 

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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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Correspondence to M. Flint Beal.

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Klivenyi, P., Ferrante, R., Matthews, R. et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 5, 347–350 (1999).

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