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The Journal of Neuroscience, June 15, 2000, 20(12):4389-4397
Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease
Robert J. Ferrante1, 2, 3, Ole A. Andreassen4, 5, Bruce G. Jenkins6, 7, Alpaslan Dedeoglu4, 5, Stefan Kuemmerle2, James K. Kubilus1, 3, Rima Kaddurah-Daouk8, Steven M. Hersch9, and M. Flint Beal4, 5, 10 1 Geriatric Research Education and Clinical Center, Bedford Veteran's Administration Medical Center, Bedford, Massachusetts 01730, 2 Neurology, Pathology, and Psychiatry Departments, and 3 Boston University School of Medicine, Boston, Massachusetts 02118, 4 Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital, and 5 Harvard Medical School, Boston, Massachusetts 02114, 6 Department of Radiology, Massachusetts General Hospital-Nuclear Magnetic Resonance Center, Massachusetts General Hospital, and 7 Harvard Medical School, Charlestown, Massachusetts 02114, 8 The Avicena Group, Inc., Cambridge, Massachusetts 02139, 9 Neurology Department, Emory University School of Medicine, Atlanta, Georgia 30322, and 10 Department of Neurology and Neuroscience, Weill Medical College of Cornell University and the New York Hospital-Cornell Medical Center, New York, New York 10021
Huntington's disease (HD) is a progressive neurodegenerative illness for which there is no effective therapy. We examined whether creatine, which may exert neuroprotective effects by increasing phosphocreatine levels or by stabilizing the mitochondrial permeability transition, has beneficial effects in a transgenic mouse model of HD (line 6/2). Dietary creatine supplementation significantly improved survival, slowed the development of brain atrophy, and delayed atrophy of striatal neurons and the formation of huntingtin-positive aggregates in R6/2 mice. Body weight and motor performance on the rotarod test were significantly improved in creatine-supplemented R6/2 mice, whereas the onset of diabetes was markedly delayed. Nuclear magnetic resonance spectroscopy showed that creatine supplementation significantly increased brain creatine concentrations and delayed decreases in N-acetylaspartate concentrations. These results support a role of metabolic dysfunction in a transgenic mouse model of HD and suggest a novel therapeutic strategy to slow the pathological process.
Key words: creatine; mitochondria; Huntington's disease; transgenic mice; diabetes; N-acetylaspartate
Copyright © 2000 Society for Neuroscience 0270-6474/00/20124389-09$05.00/0
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