Authors
Matthews RT. Yang L. Jenkins BG. Ferrante RJ. Rosen BR. Kaddurah-Daouk
R. Beal MF.
Institution
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, USA.
Title
Neuroprotective effects of creatine and
cyclocreatine in animal models of Huntington's disease.
Source
Journal of Neuroscience. 18(1):156-63, 1998 Jan 1.
Abstract
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.