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

P. Klivényi, Robert J. Ferrante, Russell T. Matthews, Mikhail B. Bogdanov, Autumn M. Klein, Ole A. Andreassen, Gerald Mueller, Marieke Wermer, Rima Kaddurah-Daouk, M. Flint Beal

Research output: Contribution to journalArticle

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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 mutations. 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 concentration. 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 consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. 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.

Original languageEnglish
Pages (from-to)347-350
Number of pages4
JournalNature Medicine
Volume5
Issue number3
DOIs
Publication statusPublished - 1999

Fingerprint

Genetically Modified Animals
Creatine
Amyotrophic Lateral Sclerosis
Neuroprotective Agents
Animals
Animal Models
Mitochondria
Transgenic Mice
Neurons
Mitochondrial Form Creatine Kinase
Mitochondrial Swelling
Mutation
Oxidative stress
Phosphocreatine
Mitochondrial Membrane Potential
Motor Neurons
Substantia Nigra
Cell death
Enzymes
Creatine Kinase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Klivényi, P., Ferrante, R. J., Matthews, R. T., Bogdanov, M. B., Klein, A. M., Andreassen, O. A., ... Beal, M. F. (1999). Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nature Medicine, 5(3), 347-350. https://doi.org/10.1038/6568

Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. / Klivényi, P.; Ferrante, Robert J.; Matthews, Russell T.; Bogdanov, Mikhail B.; Klein, Autumn M.; Andreassen, Ole A.; Mueller, Gerald; Wermer, Marieke; Kaddurah-Daouk, Rima; Beal, M. Flint.

In: Nature Medicine, Vol. 5, No. 3, 1999, p. 347-350.

Research output: Contribution to journalArticle

Klivényi, P, Ferrante, RJ, Matthews, RT, Bogdanov, MB, Klein, AM, Andreassen, OA, Mueller, G, Wermer, M, Kaddurah-Daouk, R & Beal, MF 1999, 'Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis', Nature Medicine, vol. 5, no. 3, pp. 347-350. https://doi.org/10.1038/6568
Klivényi, P. ; Ferrante, Robert J. ; Matthews, Russell T. ; Bogdanov, Mikhail B. ; Klein, Autumn M. ; Andreassen, Ole A. ; Mueller, Gerald ; Wermer, Marieke ; Kaddurah-Daouk, Rima ; Beal, M. Flint. / Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. In: Nature Medicine. 1999 ; Vol. 5, No. 3. pp. 347-350.
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