Molecular mechanism of distorted iron regulation in the blood-CSF barrier and regional blood-brain barrier following in vivo subchronic manganese exposure
Molecular mechanism of distorted iron regulation in the blood-CSF barrier and regional blood-brain barrier following in vivo subchronic manganese exposure
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DOI：
10.1016/j.neuro.2006.02.003
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发表时间：
2006-09-01
期刊：
影响因子：
3.4
通讯作者：
Zheng, Wei
中科院分区：
文献类型：
--
作者：
Li, G. Jane;Choi, Lyung-Sun;Zheng, Wei
本实验室先前的研究表明，锰（Mn）暴露在体外增加转铁蛋白受体（TfR）的表达，通过增强铁调节蛋白（IRP）的铁响应元件的RNA的结合。本研究进一步验证了以下假设：体内暴露于Mn增加了血脑屏障（BBB）和血脑脊液（CSF）屏障（BCB）处的TfR表达，这有助于改变CSF中的铁（Fe）稳态。各组大鼠（每组10-11只）接受口服灌胃，剂量为5 mg Mn/kg或15 mg Mn/kg MnCl 2，每日一次，持续30天。收集血液、CSF和脉络丛，并将脑毛细血管组分与区域实质分离。金属分析表明，口服锰暴露降低血清中的铁浓度（-66%），但增加CSF中的铁（+167%）。凝胶位移分析显示，Mn导致IRP 1与脉络丛（+70%）、纹状体（+39%）、海马（+56%）、额叶皮质（+49%）的毛细血管的局部BBB以及纹状体（+67%）、海马（+39%）和小脑（+28%）的脑实质中的BCB中的含铁响应元件的RNA的结合的剂量依赖性增加。实时荧光定量RT-PCR结果显示，染锰可显著增加脉络丛和纹状体TfR mRNA的表达，同时降低铁蛋白（Ft）mRNA的表达。总的来说，这些数据表明，在体内锰暴露的结果在体液中的铁重新分布，通过调节在BCB和选定的区域血脑屏障的TfR和铁蛋白的表达。脑屏障对铁转运的破坏可能是脑脊液铁稳态紊乱的基础。(C)2006年爱思唯尔公司All rights reserved.
Previous studies in this laboratory indicated that manganese (Mn) exposure in vitro increases the expression of transferrin receptor (TfR) by enhancing the binding of iron regulatory proteins (IRPs) to iron responsive element-containing RNA. The current study further tested the hypothesis that in vivo exposure to Mn increased TfR expression at both blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCB), which contributes to altered iron (Fe) homeostasis in the CSF. Groups of rats (10-11 each) received oral gavages at doses of 5 mg Mn/kg or 15 mg Mn/kg as MnCl2 once daily for 30 days. Blood, CSF, and choroid plexus were collected and brain capillary fractions were separated from the regional parenchyma. Metal analyses showed that oral Mn exposure decreased concentrations of Fe in serum (-66%) but increased Fe in the CSF (+167%). Gel shift assay showed that Mn caused a dose-dependent increase of binding of IRP1 to iron responsive element-containing RNA in BCB in the choroid plexus (+70%), in regional BBB of capillaries of striatum (+39%), hippocampus (+56%), frontal cortex (+49%), and in brain parenchyma of striatum (+67%), hippocampus (+39%) and cerebellum (+28%). Real-time RT-PCR demonstrated that Mn exposure significantly increased the expression of TfR mRNA in choroid plexus and striatum with concomitant reduction in the expression of ferritin (Ft) mRNA. Collectively, these data indicate that in vivo Mn exposure results in Fe redistribution in body fluids through regulating the expression of TfR and ferritin at BCB and selected regional BBB. The disrupted Fe transport by brain barriers may underlie the distorted Fe homeostasis in the CSF. (C) 2006 Elsevier Inc. All rights reserved.