Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease.
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.
Ferrante
R J
RJ
Geriatric Research Education and Clinical Center, Bedford Veteran's Administration Medical Center, Bedford, Massachusetts 01730, USA. rjferr@bu.edu
Andreassen
O A
OA
Jenkins
B G
BG
Dedeoglu
A
A
Kuemmerle
S
S
Kubilus
J K
JK
Kaddurah-Daouk
R
R
Hersch
S M
SM
Beal
M F
MF
D000818:Animals; D030801:Animals, Genetically Modified; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001284:Atrophy; D001921:Brain / Q000187:drug effects / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D003401:Creatine / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D003433:Crosses, Genetic; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D009687:Nuclear Proteins / Q000235:genetics*
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D001224:Aspartic Acid; C000179:N-acetylaspartate; D003401:Creatine