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

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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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.

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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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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). https://doi.org/10.1038/6568

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