Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase

Peter Klivenyi, Noel Y. Calingasan, Anatoly Starkov, Irina G. Stavrovskaya, Bruce S. Kristal, Lichuan Yang, Bé Wieringa, M. Flint Beal

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50 Citations (Scopus)

Abstract

There is substantial evidence that creatine administration exerts neuroprotective effects both in vitro and in vivo. The precise mechanisms for these neuroprotective effects however are as yet unclear. We investigated whether creatine administration could exert neuroprotective effects in mice deficient in ubiquitous mitochondrial creatine kinase (UbMi-CK). UbMi-CK-deficient mice showed increased sensitivity to 1-methyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopamine depletion and loss of tyrosine hydroxylase (TH) stained neurons. Isolated mitochondria from these mice showed no alterations in calcium retention, oxygen utilization, membrane potential, or swelling in response to a calcium challenge. Creatine administration significantly increased brain concentrations of both creatine and PCr in the UbMi-CK knockout mice. Creatine administration to the UbMi-CK-deficient mice exerted significant neuroprotective effects against MPTP toxicity that were comparable in magnitude to those seen in wild-type mice. These results suggest that the neuroprotective effects of creatine are not mediated by an effect on UbMi-CK to inhibit the mitochondrial permeability transition, and are more likely to be mediated by maintenance of appropriate ATP/ADP and PCr/Cr levels.

Original languageEnglish
Pages (from-to)610-617
Number of pages8
JournalNeurobiology of Disease
Volume15
Issue number3
DOIs
Publication statusPublished - Apr 1 2004

Keywords

  • Creatine
  • Creatine kinase
  • MPTP
  • Mitochondria
  • Phosphocreatine

ASJC Scopus subject areas

  • Neurology

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  • Cite this

    Klivenyi, P., Calingasan, N. Y., Starkov, A., Stavrovskaya, I. G., Kristal, B. S., Yang, L., Wieringa, B., & Beal, M. F. (2004). Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase. Neurobiology of Disease, 15(3), 610-617. https://doi.org/10.1016/j.nbd.2003.12.014