p-quinone mediates 6-hydroxydopamine-induced dopaminergic neuronal death and ferrous iron accelerates the conversion of p-quinone into melanin extracellularly
p-quinone mediates 6-hydroxydopamine-induced dopaminergic neuronal death and ferrous iron accelerates the conversion of p-quinone into melanin extracellularly
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DOI：
10.1002/jnr.20382
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发表时间：
2005-03-15
影响因子：
4.2
通讯作者：
Akaike, A
中科院分区：
文献类型：
--
作者：
Izumi, Y;Sawada, H;Akaike, A
帕金森病（PD）的特征是黑质（SN）中多巴胺能神经元的选择性丧失。6-羟基多巴胺（6-OHDA）是一种多巴胺能神经毒素，在人脑和PD患者的尿液中检测到。使用SH-SY 5 Y，一种人神经母细胞瘤细胞系，我们证明了6-OHDA毒性是由6-OHDA自氧化产生的对苯醌的量而不是活性氧（ROS）决定的。与对苯醌结合的谷胱甘肽（GSH）提供了显著的保护，而解毒过氧化氢和超氧阴离子的过氧化氢酶未能阻断6-OHDA引起的细胞死亡。虽然铁在PD患者SN中的积累可以通过增强氧化应激引起多巴胺能神经元变性，但我们发现细胞外亚铁促进黑色素的形成并减少对苯醌的量。在培养液中加入亚铁抑制caspase-3激活和凋亡的核形态学变化，并阻断6-OHDA诱导的SH-SY 5 Y细胞和原代培养的中脑多巴胺能神经元的细胞毒性。这些数据表明，对苯醌的产生在6-OHDA诱导的毒性中起着关键作用，与细胞内铁相比，细胞外铁是保护性的而不是有害的，因为它加速了对苯醌转化为黑色素。(C)2005 Wiley-Liss，Inc.
Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). 6-Hydroxydopamine (6-OHDA), a dopaminergic neurotoxin, is detected in human brains and the urine of PD patients. Using SH-SY5Y, a human neuroblastoma cell line, we demonstrated that 6-OHDA toxicity was determined by the amount of p-quinone produced in 6-OHDA auto-oxidation rather than by reactive oxygen species (ROS). Glutathione (GSH), which conjugated with p-quinone, provided significant protection whereas catalase, which detoxified hydrogen peroxide and superoxide anions, failed to block cell death caused by 6-OHDA. Although iron accumulated in the SN of patients with PD can cause dopaminergic neuronal degeneration by enhancing oxidative stress, we found that extracellular ferrous iron promoted the formation of melanin and reduced the amount of p-quinone. The addition of ferrous iron to the culture medium inhibited caspase-3 activation and apoptotic nuclear morphologic changes and blocked 6-OHDA-induced cytotoxicity in SH-SY5Y cells and primary cultured mesencephalic dopaminergic neurons. These data suggested that generation of p-quinone played a pivotal role in 6-OHDA-induced toxicity and extracellular iron in contrast to intracellular iron was protective rather than harmful because it accelerated the conversion of p-quinone into melanin. (C) 2005 Wiley-Liss, Inc.