Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase.
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.
Klivenyi
Peter
P
Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA.
Calingasan
Noel Y
NY
Starkov
Anatoly
A
Stavrovskaya
Irina G
IG
Kristal
Bruce S
BS
Yang
Lichuan
L
Wieringa
Bé
B
Beal
M Flint
MF
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000032:analysis; D000818:Animals; D001921:Brain / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003401:Creatine / Q000032:analysis / Q000494:pharmacology*; D003402:Creatine Kinase / Q000172:deficiency*; D052281:Creatine Kinase, Mitochondrial Form; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000172:deficiency*; D020267:MPTP Poisoning / Q000188:drug therapy; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010725:Phosphocreatine / Q000032:analysis / Q000187:drug effects
D007527:Isoenzymes; D018696:Neuroprotective Agents; D010725:Phosphocreatine; D015102:3,4-Dihydroxyphenylacetic Acid; D000249:Adenosine Monophosphate; D003402:Creatine Kinase; D052281:Creatine Kinase, Mitochondrial Form; D003401:Creatine; D004298:Dopamine; D006719:Homovanillic Acid