Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo.
Copper toxicity contributes to neuronal death in Wilson's disease and has been speculatively linked to the pathogenesis of Alzheimer's and prion diseases. We examined copper-induced neuronal death with the goal of developing neuroprotective strategies. Copper catalyzed an increase in hydroxyl radical generation in solution, and the addition of 20 microM copper for 22 hours to murine neocortical cell cultures induced a decrease in ATP levels and neuronal death without glial death. This selective neuronal death was associated with activation of caspase-3 and was reduced by free radical scavengers and Z-Val-Ala-Asp fluoromethylketone, consistent with free radical-mediated injury leading to apoptosis. Pyruvate dehydrogenase is especially vulnerable to inhibition by oxygen free radicals, and the upstream metabolites, pyruvate, phosphoenolpyruvate, and 2-phosphoglycerate were elevated in cortical cells after toxic exposure to copper. One approach to protecting pyruvate dehydrogenase from oxidative attack might be to enhance binding to cofactors. Addition of thiamine, dihydrolipoic acid, or pyruvate reduced copper-induced neuronal death. To test efficacy in vivo, we added 1% thiamine to the drinking water of Long Evans Cinnamon rats, an animal model of Wilson's disease. This thiamine therapy markedly extended life span from 6.0 +/- 1.6 months to greater than 16 months.
Sheline
Christian T
CT
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Choi
Eric H
EH
Kim-Han
Jeong-Sook
JS
Dugan
Laura L
LL
Choi
Dennis W
DW
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003300:Copper / Q000506:poisoning*; D004622:Embryo, Mammalian; D016166:Free Radical Scavengers / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D008136:Longevity / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans / Q000502:physiology; D013831:Thiamine / Q000494:pharmacology*; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*
D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D017665:Hydroxyl Radical; D008063:Thioctic Acid; D003300:Copper; C015144:dihydrolipoic acid; D013831:Thiamine