Melatonin attenuates methamphetamine-induced deactivation of the mammalian target of rapamycin signaling to induce autophagy in SK-N-SH cells
Melatonin attenuates methamphetamine-induced deactivation of the mammalian target of rapamycin signaling to induce autophagy in SK-N-SH cells
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DOI：
10.1111/j.1600-079x.2008.00648.x
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发表时间：
2009-03-01
影响因子：
10.3
通讯作者：
Govitrapong, Piyarat
中科院分区：
文献类型：
--
作者：
Kongsuphol, Patthara;Mukda, Sujira;Govitrapong, Piyarat
甲基苯丙胺（Methamphetamine，简称冰毒）是一种常见的滥用药物，它通过引起活性氧（reactive oxygen species， ROS）的形成、细胞凋亡和神经元损伤而损害神经末梢。自噬是一种独立于细胞凋亡的程序性细胞死亡，受哺乳动物雷帕霉素（mTOR）信号通路靶点的负调控。然而，目前尚不清楚自噬是否参与甲基苯丙胺诱导的神经毒性。因此，我们研究了甲基安非他明对自噬及其上游调控因子mTOR信号通路的影响。通过SK-N-SH多巴胺能细胞系，我们发现甲基安非他明诱导LC3-II的表达，LC3-II是一种与自噬体膜相关的蛋白，呈剂量依赖性。此外,冰毒抑制mTOR的磷酸化和下游的行动目标,真核起始因子(eIF) 4 e结合蛋白4 ebp1。褪黑素是松果体的主要分泌产物，是一种有效的天然抗氧化剂，通过多种机制改善活性氧的毒性作用。我们发现褪黑素预处理可以增强mTOR活性和4EBP1磷酸化，并保护暴露于冰毒的SK-N-SH细胞免受LC3-II的形成。这项工作证明了褪黑素作为对抗冰毒的神经保护剂的新作用。
Methamphetamine (METH) is a commonly abused drug that damages nerve terminals by causing reactive oxygen species (ROS) formation, apoptosis, and neuronal damage. Autophagy, a type of programmed cell death independent of apoptosis, is negatively regulated by the mammalian target of the rapamycin (mTOR) signaling pathway. It is not known, however, whether autophagy is involved in METH-induced neurotoxicity. Therefore, we investigated the effect of METH on autophagy and its upstream regulator, the mTOR signaling pathway. Using the SK-N-SH dopaminergic cell line, we found that METH induces the expression of LC3-II, a protein associated with the autophagosome membrane, in a dose-dependent manner. Moreover, METH inhibits the phosphorylation of mTOR and the action of its downstream target, the eukaryotic initiation factor (eIF)4E-binding protein, 4EBP1. Melatonin, a major secretory product of pineal, is a potent naturally produced antioxidant that acts through various mechanisms to ameliorate the toxic effects of ROS. We found that a pretreatment with melatonin enhances mTOR activity and 4EBP1 phosphorylation and protects against the formation of LC3-II in SK-N-SH cells exposed to METH. This work demonstrates a novel role for melatonin as a neuroprotective agent against METH.