Potential autophagy enhancers attenuate rotenone-induced toxicity in SH-SY5Y
Potential autophagy enhancers attenuate rotenone-induced toxicity in SH-SY5Y
复制标题
DOI：
10.1016/j.neuroscience.2011.10.031
复制
发表时间：
2011-12
期刊：
影响因子：
3.3
通讯作者：
N. Xiong;Min Jia;Chunnuan Chen;Jing Xiong;Zongze Zhang;Jinsha Huang;Lingling Hou;Hecheng Yang;Xuebing Cao;Zhihou Liang;Shenggang Sun;Zhicheng Lin;Tao Wang
中科院分区：
文献类型：
--
作者：
N. Xiong;Min Jia;Chunnuan Chen;Jing Xiong;Zongze Zhang;Jinsha Huang;Lingling Hou;Hecheng Yang;Xuebing Cao;Zhihou Liang;Shenggang Sun;Zhicheng Lin;Tao Wang
最近的研究表明，自噬上调可能是一种易于处理的治疗干预，用于清除帕金森病（PD）中的致病蛋白，包括α-突触核蛋白、泛素和其他错误折叠或聚集的蛋白。在这项研究中，我们探索了一种新的药物治疗PD的方法，利用潜在的自噬增强剂丙戊酸（VPA）和卡马西平（CBZ）。VPA（3 mM）和CBZ（50 μM）沿着阳性对照雷帕霉素（Rap，0.2 μM）或锂（LiCl，10 mM）预处理显著增强了人神经母细胞瘤SH-SY 5 Y细胞的细胞活力，降低了鱼藤酮诱导的核碎裂和凋亡，改善了线粒体膜电位的降低，减少了活性氧的产生。具体而言，溶酶体和自噬空泡细胞器的数量增加，微管相关蛋白1轻链3-II（LC 3-II）表达上调VPA，CBZ，Rap和LiCl（53%，31%，72%和63%），表明这些药物激活自噬途径。此外，自噬抑制剂氯喹（Chl，10 μM）的预处理显着增强鱼藤酮在这些细胞中的毒性。我们的研究结果表明，VPA和CBZ，最常用的抗癫痫和情绪稳定的药物，低风险和易于管理，可能是潜在的治疗PD。
Recent studies have shown that autophagy upregulation may be a tractable therapeutic intervention for clearing the disease-causing proteins, including α-synuclein, ubiquitin, and other misfolded or aggregated proteins in Parkinson's disease (PD). In this study, we explored a novel pharmacotherapeutic approach to treating PD by utilizing potential autophagy enhancers valproic acid (VPA) and carbamazepine (CBZ). Pretreatment with VPA (3 mM) and CBZ (50 μM) along with positive control rapamycin (Rap, 0.2 μM) or lithium (LiCl, 10 mM) significantly enhanced cell viability, decreased rotenone-induced nuclear fragmentation and apoptosis, ameliorated the decrease in mitochondrial membrane potential, reduced reactive oxygen species generation in the human neuroblastoma SH-SY5Y cells. Specifically, the numbers of lysosomes and autophagic vacuolar organelles were increased and the microtubule-associated protein 1 light chain 3-II (LC3-II) expression was up-regulated by VPA, CBZ, Rap, and LiCl (53%, 31%, 72%, and 63%), suggesting that these agents activated autophagic pathways. Moreover, pretreatment with the autophagy inhibitor chloroquine (Chl, 10 μM) remarkably strengthened rotenone toxicity in these cells. Our results suggest that VPA and CBZ, the most commonly used anti-epilepsy and mood-stabilizing medications with low-risk and easy administration might be potential therapeutics for PD.