Iron and other transition metals, such as copper and manganese, are essential for supporting brain function, yet over-accumulation is cytotoxic. This over-accumulation of metals, particularly iron, is common to several neurological disorders; these include Alzheimer's disease, Parkinson's disease, Friedrich's ataxia and other disorders presenting with neurodegeneration and associated brain iron accumulation. The management of iron flux by the blood-brain barrier provides the first line of defense against the over-accumulation of iron in normal physiology and in these pathological conditions. In this study, we determined that the iron chelator PBT434, which is currently being developed for treatment of Parkinson's disease and multiple system atrophy, modulates the uptake of iron by human brain microvascular endothelial cells (hBMVEC) by chelation of extracellular Fe2+. Treatment of hBMVEC with PBT434 results in an increase in the abundance of the transcripts for transferrin receptor (TfR) and ceruloplasmin (Cp). Western blot and ELISA analyses reveal a corresponding increase in the proteins as well. Within the cell, PBT434 increases the detectable level of chelatable, labile Fe2+; data indicate that this Fe2+ is released from ferritin. In addition, PBT434 potentiates iron efflux likely due to the increase in cytosolic ferrous iron, the substrate for the iron exporter, ferroportin. PBT434 equilibrates rapidly and bi-directionally across an hBMVEC blood-brain barrier. These results indicate that the PBT434-iron complex is not substrate for hBMVEC uptake and thus support a model in which PBT434 would chelate interstitial iron and inhibit re-uptake of iron by endothelial cells of the blood-brain barrier, as well as inhibit its uptake by the other cells of the neurovascular unit. Overall, this presents a novel and promising mechanism for therapeutic iron chelation.

中文翻译：

---

铁螯合剂 PBT434 调节脑微血管内皮细胞中的跨细胞铁运输。

铁和其他过渡金属，如铜和锰，对支持大脑功能至关重要，但过度积累会产生细胞毒性。这种金属，尤其是铁的过度积累，在几种神经系统疾病中很常见。这些包括阿尔茨海默病、帕金森病、弗里德里希共济失调和其他表现为神经变性和相关脑铁积累的疾病。血脑屏障对铁通量的管理提供了第一道防线，以防止正常生理和这些病理条件下铁的过度积累。在这项研究中，我们确定了目前正在开发用于治疗帕金森病和多系统萎缩的铁螯合剂 PBT434，通过螯合胞外 Fe2+ 调节人脑微血管内皮细胞 (hBMVEC) 对铁的吸收。用 PBT434 处理 hBMVEC 导致转铁蛋白受体 (TfR) 和铜蓝蛋白 (Cp) 转录本的丰度增加。蛋白质印迹和 ELISA 分析也揭示了蛋白质的相应增加。在细胞内，PBT434 增加了可螯合的、不稳定的 Fe2+ 的可检测水平；数据表明这种 Fe2+ 是从铁蛋白中释放出来的。此外，PBT434 可能是由于细胞溶质亚铁（铁输出体的底物铁转运蛋白的底物）的增加而增强铁流出。PBT434 通过 hBMVEC 血脑屏障快速双向平衡。这些结果表明 PBT434-铁复合物不是 hBMVEC 摄取的底物，因此支持 PBT434 将螯合间质铁并抑制血脑屏障内皮细胞对铁的再摄取以及抑制其摄取的模型由神经血管单位的其他细胞。总体而言，这为治疗性铁螯合提供了一种新颖且有前景的机制。