title: Methamphetamine decreases levels of glutathione peroxidases 1 and 4 in SH-SY5Y neuronal cells: protective effects of selenium.
abstract: 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 100 nM selenium, and then challenged the cells with a 24-h exposure to methamphetamine. We found that 100 μM 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 0 nM 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.
authors.affiliation: Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, HI 96813, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Barayuga
authors.forename: Xiaosha
authors.initials: X
authors.lastname: Pang
authors.forename: Marilou A
authors.initials: MA
authors.lastname: Andres
authors.forename: Jun
authors.initials: J
authors.lastname: Panee
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Bellinger
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D008694:Methamphetamine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D017382:Reactive Oxygen Species / Q000378:metabolism; D018038:Sodium Selenite / Q000494:pharmacology*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000697:Central Nervous System Stimulants; D017382:Reactive Oxygen Species; D008694:Methamphetamine; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D005978:Glutathione; D018038:Sodium Selenite; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human