Methamphetamine decreases levels of glutathione peroxidases 1 and 4 in SH-SY5Y neuronal cells: protective effects of selenium.
Methamphetamine decreases levels of glutathione peroxidases 1 and 4 in SH-SY5Y neuronal cells: protective effects of selenium.
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DOI：
10.1016/j.neuro.2013.05.009
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发表时间：
2013-07
期刊：
影响因子：
3.4
通讯作者：
Bellinger, Frederick P.
中科院分区：
文献类型：
--
作者：
Barayuga, Stephanie M.;Pang, Xiaosha;Andres, Marilou A.;Panee, Jun;Bellinger, Frederick P.
甲基苯丙胺会干扰多巴胺的再摄取，从而导致多巴胺氧化增加，从而产生氧化应激，从而导致多巴胺能末端退化。先前的研究表明，微量元素硒可以防止甲基苯丙胺中毒。然而，负责保护的特定硒蛋白尚未阐明。谷胱甘肽过氧化物酶 1 和 4（GPx1 和 GPx4）将硒结合到氨基酸硒代半胱氨酸中，它们已知的抗氧化功能使它们成为防止甲基苯丙胺诱导的氧化损伤的良好候选者。我们在含有 0、10 和 100 nM 硒的规定补充剂的无血清培养基中分化了 SH-SY5Y 神经元细胞，然后将细胞暴露于甲基苯丙胺 24 小时。我们发现 100 μM 甲基苯丙胺降低了 GPx1 和 GPx4 蛋白水平。然而，随着培养基硒浓度的增加，这两种蛋白质均上调。硒也增加了 GPx 酶活性，甲基苯丙胺则降低了 GPx 酶活性，并且与 GPx 蛋白水平相关。在较低的硒含量条件下，甲基苯丙胺降低了总谷胱甘肽水平，而在较高的硒含量条件下，谷胱甘肽的氧化部分增加。此外，我们观察到在含有 0 nM 硒的介质中暴露于甲基苯丙胺后，活性氧的产生增加，通过补充硒可以改善这种情况。这些结果表明，甲基苯丙胺通过降低 GPx 水平来增加氧化应激，并且可以通过添加硒来逆转这种情况。这些发现对于治疗急性甲基苯丙胺中毒患者具有重要意义。
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-hour 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.
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