Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease.
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.
Matthews
R T
RT
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.
Yang
L
L
Jenkins
B G
BG
Ferrante
R J
RJ
Rosen
B R
BR
Kaddurah-Daouk
R
R
Beal
M F
MF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003401:Creatine / Q000494:pharmacology*; D003404:Creatinine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000494:pharmacology; D017072:Neostriatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D005609:Free Radicals; D007773:Lactates; D008314:Malonates; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; C002744:3-nitrotyrosine; D014443:Tyrosine; C012260:cyclocreatine; D000255:Adenosine Triphosphate; C030290:malonic acid; D003404:Creatinine; D003401:Creatine; C015392:3-nitropropionic acid