title: Copper increases the ability of 6-hydroxydopamine to generate oxidative stress and the ability of ascorbate and glutathione to potentiate this effect: potential implications in Parkinson's disease.
abstract: Copper is an essential metal for the function of many proteins related to important cellular reactions and also involved in the synaptic transmission. Although there are several mechanisms involved in copper homeostasis, a dysregulation in this process can result in serious neurological consequences, including degeneration of dopaminergic neurons. 6-Hydroxydopamine is a dopaminergic neurotoxin mainly used in experimental models of Parkinson's disease, whose neurotoxicity has been related to its ability to generate free radicals. In this study, we examined the effects induced by copper on 6-OHDA autoxidation. Our data show that both Cu+and Cu2+caused an increase in•OH production by 6-OHDA autoxidation, which was accompanied by an increase in the rate of both p-quinone formation and H2O2accumulation. The presence of ascorbate greatly enhanced this process by establishing a redox cycle which regenerates 6-OHDA from its p-quinone. However, the presence of glutathione did not change significantly the copper-induced effects. We observed that copper is able to potentiate the ability of 6-OHDA to cause both lipid peroxidation and protein oxidation, with the latter including a reduction in free-thiol content and an increase in carbonyl content. Ascorbate also increases the lipid peroxidation induced by the action of copper and 6-OHDA. Glutathione protects against the copper-induced lipid peroxidation, but does not reduce its potential to oxidize free thiols. These results clearly demonstrate the potential of copper to increase the capacity of 6-OHDA to generate oxidative stress and the ability of ascorbate to enhance this potential, which may contribute to the destruction of dopaminergic neurons.
authors.affiliation: Laboratory of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Antón
authors.initials: A
authors.lastname: Cruces-Sande
authors.affiliation: Laboratory of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Méndez-Álvarez
authors.affiliation: Laboratory of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.|Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Ramón
authors.identifier: 0000-0003-0079-0279
authors.initials: R
authors.lastname: Soto-Otero
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D001921:Brain / Q000648:ultrastructure; D003300:Copper / Q000494:pharmacology*; D004357:Drug Synergism; D005978:Glutathione / Q000493:pharmacokinetics*; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D018663:Adrenergic Agents; D000975:Antioxidants; D003300:Copper; D016627:Oxidopamine; D006861:Hydrogen Peroxide; D005978:Glutathione; D001205:Ascorbic Acid
keywords: 6-hydroxydopamine; ascorbate; copper; glutathione; oxidative stress