The role of selenoproteins in protection against methamphetamine-induced dopaminergic neurodegeneration
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2014-05
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University of Hawaii at Manoa
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Methamphetamine (MA) increases oxidative stress through actions on dopaminergic transmission. Selenium (Se) is an antioxidant trace element that is necessary for normal brain functions. Previous studies have shown that Se protects against MA neurotoxicity and is necessary for proper dopamine function. The specific aim of the project is to determine the role of antioxidant selenoproteins, including the glutathione peroxidases (GPXs), in protecting dopaminergic neurons from MA toxicity in vitro and in vivo. In SH-SY5Y cells, MA decreased protein levels for GPX1 and GPX4. However, both proteins were upregulated with increasing Se concentration. GPX enzymatic activity was increased by Se concentrations and decreased by MA and correlated with GPX protein levels. MA reduced total intracellular GSH levels at lower Se concentrations, while the oxidized fraction of GSH was increased at higher Se levels. Extracellular GSH was increased in 0 nM Se only, with no changes from MA or any changes in the oxidized fraction of GSH. Additionally, MA increased ROS levels in cell cultures grown in 0 nM Se, but Se supplementation prevented the increase. Our in vivo results show that GPX1 and GPX4 increase with Se, whereas, DAT and TH expression do not appear to change. The results of our study indicate that a MA-induced reduction in GPX levels can contribute to increased oxidative stress. GPX reduction can be prevented increasing Se levels. These findings have important implications for treating patients with acute methamphetamine toxicity.
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selenoproteins
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Theses for the degree of Master of Science (University of Hawaii at Manoa). Molecular Biosciences and Bioengineering.
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