The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
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DOI：
10.1371/journal.pone.0254794
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Kosman DJ
中科院分区：
文献类型：
--
作者：
Bailey DK;Clark W;Kosman DJ
铁和其他过渡金属，例如铜和锰，对于支持大脑功能至关重要，但过度积累具有细胞毒性。这种金属（尤其是铁）的过度积累是多种神经系统疾病的常见现象。这些疾病包括阿尔茨海默病、帕金森病、弗里德里希共济失调和其他表现为神经退行性变和相关脑铁积累的疾病。血脑屏障对铁通量的管理提供了防止正常生理和这些病理条件下铁过度积累的第一道防线。在这项研究中，我们确定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 通过螯合细胞外 Fe2+ 来调节人脑微血管内皮细胞 (hBMVEC) 对铁的吸收。用 PBT434 处理 hBMVEC 会导致转铁蛋白受体 (TfR) 和铜蓝蛋白 (Cp) 转录本的丰度增加。蛋白质印迹和 ELISA 分析显示蛋白质也相应增加。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 增强铁流出可能是由于胞质亚铁（铁输出蛋白铁转运蛋白的底物）的增加所致。 PBT434 穿过 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，因此支持这样的模型：PBT434 将螯合间质铁并抑制血脑屏障的内皮细胞对铁的再摄取，以及抑制神经血管单元的其他细胞对铁的摄取。总的来说，这为治疗性铁螯合提供了一种新颖且有前途的机制。
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.
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影响因子：
3.5
作者：
Gaboriau, Francois;Leray, Anne-Marie;Lescoat, Gerard
通讯作者：
Lescoat, Gerard
影响因子：
11.4
作者：
De Domenico, Ivana;Vaughn, Michael B.;Kaplan, Jerry
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Kaplan, Jerry
影响因子：
20.3
作者：
Aschemeyer, Sharraya;Qiao, Bo;Nemeth, Elizabeta
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Nemeth, Elizabeta
影响因子：
7.3
作者：
Eigenmann DE;Xue G;Kim KS;Moses AV;Hamburger M;Oufir M
通讯作者：
Oufir M
影响因子：
7.1
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Finkelstein DI;Billings JL;Adlard PA;Ayton S;Sedjahtera A;Masters CL;Wilkins S;Shackleford DM;Charman SA;Bal W;Zawisza IA;Kurowska E;Gundlach AL;Ma S;Bush AI;Hare DJ;Doble PA;Crawford S;Gautier EC;Parsons J;Huggins P;Barnham KJ;Cherny RA
通讯作者：
Cherny RA