Insulin-like growth factor binding protein 5 (IGFBP5) mediates methamphetamine-induced dopaminergic neuron apoptosis
Insulin-like growth factor binding protein 5 (IGFBP5) mediates methamphetamine-induced dopaminergic neuron apoptosis
复制标题
胰岛素样生长因子结合蛋白 5 (IGFBP5) 介导甲基苯丙胺诱导的多巴胺能神经元凋亡
DOI：
10.1016/j.toxlet.2014.08.010
复制
发表时间：
2014-11-04
影响因子：
3.5
通讯作者：
Wang, Huijun
中科院分区：
文献类型：
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作者：
Qiao, Dongfang;Xu, Jingtao;Wang, Huijun
过度暴露于甲基苯丙胺（冰毒），一种精神活性药物，会对神经系统产生多种不良影响，包括多巴胺能神经元的凋亡。胰岛素样生长因子结合蛋白5 （Insulin-like growth factor binding protein 5, IGFBP5）是胰岛素样生长因子（Insulin-like growth factor， IGF）系统的成员，是一种促凋亡因子，在神经元凋亡中起重要作用。为了验证IGFBP5可以介导甲基安非他明诱导的神经元凋亡的假设，我们检测了暴露于甲基安非他明（3.0 mM） 24 h的PC12细胞和间隔12 h腹腔注射15 mg/kg × 8次甲基安非他明后大鼠纹状体中IGFBP5 mRNA和蛋白的表达变化。通过TUNEL染色和流式细胞术检测IGFBP5表达沉默后对神经元凋亡的影响；Western blot检测凋亡标志物active-caspase3、PARP的表达。为了阐明IGFBP5介导的神经元凋亡的机制，我们测定了在甲基甲氧基甲基化处理（或不敲低IGFBP5）后线粒体中细胞色素c （cyto c）的释放，这是一种凋亡因子。结果显示，甲基安非他明暴露后，PC12细胞和经甲基安非他明处理的大鼠纹状体中IGFBP5的表达显著增加。此外，与对照细胞相比，暴露于meth的PC12细胞表现出更高的凋亡阳性细胞数量和caspase3和PARP的活性，而这些变化可以通过沉默IGFBP5的表达来阻断。此外，甲基安非他明暴露后，PC12细胞线粒体中细胞c的释放显著增加，而沉默IGFBP5表达后，细胞c的释放被抑制。这些结果表明，IGFBP5在甲基醚诱导的神经元凋亡中起关键作用，可能是甲基醚引起的神经毒性治疗的潜在基因靶点。2014爱思唯尔爱尔兰有限公司版权所有。
Overexposure to methamphetamine (METH), a psychoactive drug, induces a variety of adverse effects to the nervous system, including apoptosis of dopaminergic neurons. Insulin-like growth factor binding protein 5 (IGFBP5), a member of insulin-like growth factor (IGF) system, is a pro-apoptotic factor that plays important roles in neuronal apoptosis. To test the hypothesis that IGFBP5 can mediate METH-induced neuronal apoptosis, we examined IGFBP5 mRNA and protein expression changes in PC12 cells exposed to METH (3.0 mM) for 24 h and in the striatum of rats following 15 mg/kg x 8 intraperitoneal injections of METH at 12 h interval. We also checked the effect on neuronal apoptosis after silencing IGFBP5 expression with TUNEL staining and flow cytometry; Western blot was used for detecting the expression of apoptotic markers active-caspase3 and PARP. To elucidate the mechanisms underlying IGFBP5-mediated neuronal apoptosis, we determined the release of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria after METH treatment with or without IGFBP5 knockdown. Our results showed that IGFBP5 expression was increased significantly after METH exposure in PC12 cells and in the METH-treated rats' striatum. Further, METH-exposed PC12 cells exhibited higher apoptosis-positive cell number and activity of caspase3 and PARP compared with control cells, while these changes can be blocked by silencing IGFBP5 expression. In addition, a significant increase of cyto c release from mitochondria after METH exposure was observed and it was inhibited after silencing IGFBP5 expression in PC12 cells. These results indicate that IGFBP5 plays key roles in METH-induced neuronal apoptosis and may be a potential gene target for therapeutics in METH-caused neurotoxicity. (C) 2014 Elsevier Ireland Ltd. All rights reserved.