Lithium protects againstmethamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway
Lithium protects againstmethamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway
复制标题
锂通过 Akt/GSK3β/mTOR 途径防止 PC12 细胞中甲基苯丙胺诱导的神经毒性
DOI：
10.1016/j.bbrc.2015.08.005
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Wu J;Zhu D;Zhang J;Li G;Liu Z;Sun J
甲基苯丙胺（MA）具有神经毒性，尤其是在多巴胺能神经元中。长期暴露于MA会导致精神病并增加帕金森病的风险。锂（Li）是一种已知的情绪稳定剂，具有神经保护作用。已有研究表明MA暴露可降低Akt/GSK 3 β通路的磷酸化水平，而Li则可促进Akt/GSK 3 β通路的磷酸化。此外，GSK 3 β和mTOR参与精神兴奋剂诱导的运动敏化，并且mTOR在MA诱导的毒性中起关键作用。然而，MA对Akt/GSK 3 β/mTOR通路的影响尚未在体外充分研究。在此，我们发现MA暴露显著地使PC 12细胞中Akt/GSK 3 β/mTOR通路去磷酸化。此外，Li可显著减弱MA暴露对Akt/GSK 3 β/mTOR通路的去磷酸化作用。Li对MA的毒性有明显的保护作用，而Akt抑制剂LY 294002可抑制Li的保护作用。总之，MA暴露在体外使Akt/GSK 3 β/mTOR通路去磷酸化，而锂通过Akt/GSK 3 β/mTOR通路的磷酸化来保护MA诱导的神经毒性。
Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3β pathwayin vivo,whereas Li facilitates the phosphorylation of Akt/GSK3β pathway. Moreover, GSK3β and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3β/mTOR pathway has not been fully investigatedin vitro. Here, we found that MA exposure significantly dephosphorylated Akt/GSK3β/mTOR pathway in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3β/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3β/mTOR pathwayin vitro, while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3β/mTOR pathway.