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

• Published in: Journal of neurochemistry 2017-06, Vol.141 (5), p.738-749
• Main Authors: Cruces‐Sande, Antón, Méndez‐Álvarez, Estefanía, Soto‐Otero, Ramón
• Format: Article
• Language: English
• Subjects: 6-Hydroxydopamine; Adrenergic Agents - pharmacology; Animals; Antioxidants - pharmacology; ascorbate; Ascorbic acid; Ascorbic Acid - pharmacology; Autoxidation; Brain - ultrastructure; Carbonyls; Copper; Copper - pharmacology; Degeneration; Dopamine; Dopamine receptors; Drug Synergism; Free radicals; Glutathione; Glutathione - pharmacokinetics; Homeostasis; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; Male; Mitochondria - drug effects; Mitochondria - metabolism; Movement disorders; Neurochemistry; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurotoxicity; Oxidation; Oxidation-Reduction; Oxidative stress; Oxidative Stress - drug effects; Oxidopamine - pharmacology; Oxygen Consumption - drug effects; Parkinson's disease; Peroxidation; Proteins; Quinones; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Synaptic transmission; Thiols; Time Factors; Toxins
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14019

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 H2O2 accumulation. 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. Copper catalyzes 6‐OHDA autoxidation and increases the production of •OH, H2O2, TBARS, and protein oxidation. Its combination with ascorbate enhances •OH, H2O2, TBARS, and protein free‐thiol oxidation. However, glutathione decreases both H2O2 and TBARS. Consequently, copper has the potential to increase the oxidative damage induced by 6‐OHDA, which is enhanced by ascorbate and only partially limited by glutathione.