Huntington's disease (HD) is a progressive and fatal neurologic disorder caused by an expanded CAG repeat in gene coding for a protein of unknown function that has been named huntington. The exact cause of neuronal death in HD is unknown, however, the leading hypothesis is that of excitotoxicity and apoptosis induced by a defect in energy metabolism that may be caused by oxidative stress. We previously demonstrated that mitochondrial inhibitors produce striatal lesions closely mimicking the phenotype of HD. We have also shown that oxidative injury is involved in these models and may be in human HD. Because of this research, there as been increasing interest in the HD field in exploring complementary agents that might prevent oxidative injury, Creatine is a widely used dietary supplement principally taken to enhance athletic performance. It is a very strong candidate neuroprotective agent for HD and other neurodegenerative disorders because of its ability to ameliorate toxin-based animal models and because of our preliminary evidence in transgenic HD mice. However, there is only limited animal experience with creatine and there has not yet been any trials in humans with neurodegenerative disorders. There are several potential mechanisms by which creatine could be an effective treatment for HD. First, there is evidence that it can be neuroprotective by relieving oxidative stress. Second, it could directly inhibit apoptotic neuronal death through its inhibitory action on the mitochondrial transition pore. Third, we have preliminary evidence that creatine treatment may be associated with reduced huntingtin aggregation, a potentially toxic process. Finally it could act peripherally to help reverse the weakness and muscle mass loss that is a major clinical problem in HD. We have preliminary evidence that creatine can extend survival in transgenic models of HD and that it can reduce brain markers of metabolic stress in humans with HD. We propose to test whether creatine can ameliorate the behavioral and neuropathologic phenotypes occurring intransgenic models of HD, examine the potential mechanisms of creatine neuroprotection, test its safety and tolerability in HD patients, and collect pilot clinical data examining how creatine impacts HD symptoms and progression. These studies are intended to provide the basis of a subsequent phase III trial of creatine in HD.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
1R01AT000613-01
Application #
6336094
Study Section
Special Emphasis Panel (ZRG1-SSS-9 (22))
Program Officer
Pearson, Nancy
Project Start
2000-09-01
Project End
2001-06-30
Budget Start
2000-09-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$320,562
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Rosas, Herminia D; Doros, Gheorghe; Gevorkian, Sona et al. (2014) PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology 82:850-7
Rosas, H Diana; Chen, Y Iris; Doros, Gheorghe et al. (2012) Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Arch Neurol 69:887-93
Rosas, H Diana; Salat, David H; Lee, Stephanie Y et al. (2008) Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity. Brain 131:1057-68
Fox, Jonathan H; Kama, Jibrin A; Lieberman, Gregory et al. (2007) Mechanisms of copper ion mediated Huntington's disease progression. PLoS One 2:e334
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Hersch, S M; Gevorkian, S; Marder, K et al. (2006) Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Neurology 66:250-2
Rosas, H Diana; Tuch, David S; Hevelone, Nathanael D et al. (2006) Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures. Mov Disord 21:1317-25
Qiu, Zhihua; Norflus, Fran; Singh, Bhupinder et al. (2006) Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective. J Biol Chem 281:16672-80
Ryu, Hoon; Ferrante, Robert J (2005) Emerging chemotherapeutic strategies for Huntington's disease. Expert Opin Emerg Drugs 10:345-63

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