Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, No. 308 Ningxia Road, Qingdao, 266071, China.
Biometals. 2013 Oct;26(5):705-14. doi: 10.1007/s10534-013-9647-x. Epub 2013 Jun 17.
It is well known that disrupted brain iron homeostasis was involved in Parkinson's disease. We previously reported 6-hydroxydopamine (6-OHDA) could enhance iron influx and attenuate iron efflux process, thus promote iron accumulation in neurons. Astrocytes, the major glial cell type in the central nervous system, are largely responsible for iron distribution in the brain. However, how iron metabolism changes in astrocytes with 6-OHDA treatment are not fully elucidated. In the present study, we first observed that both iron influx and efflux were enhanced with 10 μM 6-OHDA treatment for 24 h in primary cultured astrocytes. In accordance with these iron traffic modulations, both mRNA and protein levels of iron importer divalent metal transporter 1 with iron responsive element (DMT1+IRE) and exporter ferroportin 1 (FPN1) were up-regulated in these cells. L-ferritin mRNA levels were increased. Iron regulatory protein 1 (IRP1) showed a dynamic regulation with 6-OHDA treatment, as indicated by a moderate up-regulation at 12 h, however, down-regulation at 24 h. We further demonstrated that 6-OHDA treatment could induce activation of nuclear factor-kappaB (NF-κB) p65. IκBα activation inhibitor BAY11-7082 fully blocked 6-OHDA induced NF-κB p65 phosphorylation and DMT1 + IRE up-regulation. These results suggest that 6-OHDA might promote iron transport rate in astrocytes by regulating iron transporters, IRP1 expression and NF-κB p65 activation, indicating a different response between neurons and astrocytes.
众所周知，大脑铁稳态失衡与帕金森病有关。我们之前的研究报告表明，6-羟基多巴胺（6-OHDA）可以增强铁内流并减弱铁外流过程，从而促进神经元中铁的积累。星形胶质细胞是中枢神经系统中的主要神经胶质细胞类型，对大脑中的铁分布起着重要作用。然而，6-OHDA 处理后星形胶质细胞中铁代谢如何变化尚不完全清楚。在本研究中，我们首先观察到，在原代培养的星形胶质细胞中，用 10 μM 6-OHDA 处理 24 小时后，铁内流和外流均增强。与这些铁运输调节一致，铁摄取体二价金属转运蛋白 1 与铁反应元件（DMT1+IRE）和铁输出蛋白 Ferroportin 1（FPN1）的 mRNA 和蛋白水平均上调。L-铁蛋白的 mRNA 水平也增加。铁调节蛋白 1（IRP1）在 6-OHDA 处理时表现出动态调节，在 12 小时时表现出适度上调，然而在 24 小时时下调。我们进一步证明，6-OHDA 处理可以诱导核因子-κB（NF-κB）p65的激活。IκBα激活抑制剂 BAY11-7082 完全阻断了 6-OHDA 诱导的 NF-κB p65 磷酸化和 DMT1+IRE 的上调。这些结果表明，6-OHDA 可能通过调节铁转运体、IRP1 表达和 NF-κB p65 激活来促进星形胶质细胞中铁的转运率，表明神经元和星形胶质细胞之间存在不同的反应。
