Methamphetamine decreases levels of glutathione peroxidases 1 and 4 in SH-SY5Y neuronal cells: Protective effects of selenium

• Published in: Neurotoxicology (Park Forest South) 2013-07, Vol.37, p.240-246
• Main Authors: Barayuga, Stephanie M., Pang, Xiaosha, Andres, Marilou A., Panee, Jun, Bellinger, Frederick P.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Line, Tumor; Cell Survival - drug effects; Central Nervous System Stimulants - toxicity; Cytoprotection; Dopamine; Dose-Response Relationship, Drug; Down-Regulation; Glutathione; Glutathione - metabolism; Glutathione peroxidase; Glutathione Peroxidase - metabolism; Glutathione Peroxidase GPX1; Humans; Medical sciences; Methamphetamine; Methamphetamine - toxicity; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Neuropharmacology; Oxidative stress; Oxidative Stress - drug effects; Pharmacology. Drug treatments; Phospholipid Hydroperoxide Glutathione Peroxidase; Prevention and actions; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Public health. Hygiene; Public health. Hygiene-occupational medicine; Reactive Oxygen Species - metabolism; Selenium; Sodium Selenite - pharmacology; Toxicology
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2013.05.009

•Methamphetamine decreased GPx1 and GPx4 enzymes in SH-SY5Y neuronal cells.•GPx1 and GPx4 increased with increasing culture media selenium concentrations.•Methamphetamine induced changes in glutathione levels and oxidized glutathione.•The oxidized fraction of glutathione was increased with higher media selenium levels.•Glutathione changes were dependent upon selenium concentrations.•Methamphetamine increased reactive oxygen species in low but not high selenium. Methamphetamine interferes with dopamine reuptake, and the resulting increased dopamine oxidation that creates oxidative stress can lead to degeneration of dopaminergic terminals. Previous studies have shown that the trace element selenium protects against methamphetamine toxicity. However, the specific selenoproteins responsible for protection have not been elucidated. Glutathione peroxidases 1 and 4 (GPx1 and GPx4) incorporate selenium into the amino acid selenocysteine, and their known antioxidant functions make them good candidates for protection from methamphetamine-induced oxidative damage. We differentiated SH-SY5Y neuronal cells in serum-free media with defined supplement containing 0, 10 and 100nM selenium, and then challenged the cells with a 24-h exposure to methamphetamine. We found that 100μM methamphetamine decreased GPx1 and GPx4 protein levels. However, both proteins were upregulated with increasing media selenium concentration. GPx enzymatic activity was also increased by selenium and decreased by methamphetamine and correlated with GPx protein levels. Total glutathione levels were reduced by methamphetamine at lower selenium conditions, while the oxidized fraction of GSH was increased at higher selenium levels. Additionally, we observed an increased generation of reactive oxygen species with methamphetamine exposure in media with 0nM selenium, which was ameliorated by selenium supplementation. These results show that methamphetamine increases oxidative stress by reducing GPx levels, and this can be reversed with addition of selenium. These findings have important implications for treating patients with acute methamphetamine toxicity.