NEUROPROTECTIVE EFFECTS OF CREATINE AND CYCLOCREATINE IN ANIMAL-MODELS OF HUNTINGTONS-DISEASE

The gene defect in Huntington's disease (HD) may result in an impairme nt of energy metabolism. Malonate and 3-nitropropionic acid (3-NP) are inhibitors of succinate dehydrogenase that produce energy depletion a nd lesions that closely resemble those of HD. Oral supplementation wit h creatine or cyclocreatine, which are substrates for the enzyme creat ine kinase, may increase phosphocreatine (PCr) or phosphocyclocreatine (PCCr) levels and ATP generation and thereby may exert neuroprotectiv e effects. We found that oral supplementation with either creatine or cyclocreatine produced significant protection against malonate lesions , and that creatine but not cyclocreatine supplementation significantl y protected against 3-NP neurotoxicity. Creatine and cyclocreatine inc reased brain concentrations of PCr and PCCr, respectively, and creatin e protected against depletions of PCr and ATP produced by 3-NP. Creati ne supplementation protected against 3-NP induced increases in striata l lactate concentrations in vivo as assessed by H-1 magnetic resonance spectroscopy. Creatine and cyclocreatine protected against malonate-i nduced increases in the conversion of salicylate to 2,3- and 2,5-dihyd roxybenzoic acid, biochemical markers of hydroxyl radical generation. Creatine administration protected against 3-NP-induced increases in 3- nitrotyrosine concentrations, a marker of peroxynitrite-mediated oxida tive injury. Oral supplementation with creatine or cyclocreatine resul ts in neuroprotective effects in vivo, which may represent a novel the rapeutic strategy for HD and other neurodegenerative diseases.