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The Journal of Neuroscience, January 1, 1998, 18(1):156-163
Neuroprotective Effects of Creatine and Cyclocreatine in Animal
Models of Huntington's Disease
Russell T.
Matthews1,
Lichuan
Yang1,
Bruce G.
Jenkins1,
Robert J.
Ferrante2,
Bruce R.
Rosen1,
Rima
Kaddurah-Daouk3, and
M. Flint
Beal1
1 Neurochemistry Laboratory, Neurology Service and
Massachusetts General Hospital Nuclear Magnetic Resonance Center,
Department of Radiology, Massachusetts General Hospital and Harvard
Medical School, Boston, Massachusetts 02114, 2 Geriatric
Research Educational and Clinical Center, Bedford Veterans
Administration Medical Center, Department of Neurology and Pathology,
Boston University School of Medicine, Boston, Massachusetts 02115, and
3 The Avicena Group, Inc., Cambridge, Massachusetts 02139
The gene defect in Huntington's disease (HD) may result in an
impairment of energy metabolism. Malonate and 3-nitropropionic acid
(3-NP) are inhibitors of succinate dehydrogenase that produce energy
depletion and lesions that closely resemble those of HD. Oral
supplementation with creatine or cyclocreatine, which are substrates
for the enzyme creatine kinase, may increase phosphocreatine (PCr) or
phosphocyclocreatine (PCCr) levels and ATP generation and thereby may
exert neuroprotective effects. We found that oral supplementation with
either creatine or cyclocreatine produced significant protection
against malonate lesions, and that creatine but not cyclocreatine
supplementation significantly protected against 3-NP neurotoxicity.
Creatine and cyclocreatine increased brain concentrations of PCr and
PCCr, respectively, and creatine protected against depletions of PCr
and ATP produced by 3-NP. Creatine supplementation protected against
3-NP induced increases in striatal lactate concentrations in
vivo as assessed by 1H magnetic resonance
spectroscopy. Creatine and cyclocreatine protected against
malonate-induced increases in the conversion of salicylate to 2,3- and
2,5-dihydroxybenzoic acid, biochemical markers of hydroxyl radical
generation. Creatine administration protected against 3-NP-induced
increases in 3-nitrotyrosine concentrations, a marker of
peroxynitrite-mediated oxidative injury. Oral supplementation with
creatine or cyclocreatine results in neuroprotective effects in
vivo, which may represent a novel therapeutic strategy for HD
and other neurodegenerative diseases.
Key words:
creatine; ATP; oxidative injury; 3-nitrotyrosine; 3-nitropropionic acid; Huntington
Copyright © 1998 Society for Neuroscience 0270-6474/98/181156-08$05.00/0
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