Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage.
Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage.
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DOI：
10.1016/j.redox.2017.11.026
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发表时间：
2018-05
期刊：
影响因子：
11.4
通讯作者：
Gasull T
中科院分区：
文献类型：
--
作者：
DeGregorio-Rocasolano N;Martí-Sistac O;Ponce J;Castelló-Ruiz M;Millán M;Guirao V;García-Yébenes I;Salom JB;Ramos-Cabrer P;Alborch E;Lizasoain I;Castillo J;Dávalos A;Gasull T
尽管转铁蛋白是体液中铁的主要循环载体，并且已知铁过载条件通过活性氧（ROS）诱导的损伤使中风结果恶化，但是血液转铁蛋白饱和度（TSAT）对中风脑损伤的贡献是未知的。本研究的目的是获得TSAT是否确定实验性缺血性脑卒中对脑损伤的影响以及无铁转铁蛋白（apotransferrin，ATf）诱导的TSAT减少是否具有神经保护作用的证据。我们发现，实验性缺血性中风促进早期外渗的循环铁载转铁蛋白（全转铁蛋白，HTF）缺血脑实质。在体外，HTf被发现可以促进ROS的产生，并且对暴露于氧和葡萄糖剥夺的原代神经元培养物有害。在中风大鼠，而增加TSAT与外源性HTF是有害的，外源性ATF和随后的减少TSAT的管理是神经保护。从机制上讲，ATf并不能阻止HTf溢出到缺血性中风大鼠的脑实质中。然而，ATf在体外减少NMDA诱导的HTf的神经元摄取，以及NMDA介导的脂质过氧化衍生的4-HNE和由此产生的神经元死亡，而不改变NMDA受体下游的Ca 2 +-钙调磷酸酶信号传导。从培养基中去除转铁蛋白或阻断转铁蛋白受体可减少神经元死亡。总之，我们的数据表明，血液TSAT发挥了关键作用，在实验性中风引起的脑损伤。此外，我们的研究结果表明，ATf在神经元水平上的保护作用在于防止NMDA诱导的HTf摄取和ROS产生，这反过来又减少了神经元损伤。血TSAT是决定大鼠中风模型神经元命运的关键。在缺血期间，血转铁蛋白外渗并在缺血神经元中积累。全转铁蛋白（HTf）增加TSAT是有害的中风大鼠模型。用脱铁转铁蛋白（ATf）降低TSAT在大鼠中风模型中是有益的HTf促进和ATf减少ROS、铁和NMDAR引发的缺血性神经元死亡。
Despite transferrin being the main circulating carrier of iron in body fluids, and iron overload conditions being known to worsen stroke outcome through reactive oxygen species (ROS)-induced damage, the contribution of blood transferrin saturation (TSAT) to stroke brain damage is unknown. The objective of this study was to obtain evidence on whether TSAT determines the impact of experimental ischemic stroke on brain damage and whether iron-free transferrin (apotransferrin, ATf)-induced reduction of TSAT is neuroprotective. We found that experimental ischemic stroke promoted an early extravasation of circulating iron-loaded transferrin (holotransferrin, HTf) to the ischemic brain parenchyma. In vitro, HTf was found to boost ROS production and to be harmful to primary neuronal cultures exposed to oxygen and glucose deprivation. In stroked rats, whereas increasing TSAT with exogenous HTf was detrimental, administration of exogenous ATf and the subsequent reduction of TSAT was neuroprotective. Mechanistically, ATf did not prevent extravasation of HTf to the brain parenchyma in rats exposed to ischemic stroke. However, ATf in vitro reduced NMDA-induced neuronal uptake of HTf and also both the NMDA-mediated lipid peroxidation derived 4-HNE and the resulting neuronal death without altering Ca2+-calcineurin signaling downstream the NMDA receptor. Removal of transferrin from the culture media or blockade of transferrin receptors reduced neuronal death. Together, our data establish that blood TSAT exerts a critical role in experimental stroke-induced brain damage. In addition, our findings suggest that the protective effect of ATf at the neuronal level resides in preventing NMDA-induced HTf uptake and ROS production, which in turn reduces neuronal damage. Blood TSAT is pivotal to determine neuronal fate in rat models of stroke During ischemia blood transferrin extravasates and accumulates in ischemic neurons. Increasing TSAT with holotransferrin (HTf) is detrimental in rat models of stroke. Decreasing TSAT with apotransferrin (ATf) is beneficial in rat models of stroke HTf promotes and ATf reduces ROS-, iron- and NMDAR-initiated ischemic neuronal death.
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影响因子：
9.9
作者：
Dávalos, A;Castillo, J;Rama, R
通讯作者：
Rama, R
影响因子：
19.6
作者：
Agarwal, R
通讯作者：
Agarwal, R
影响因子：
158.5
作者：
Adams, PC;Reboussin, DM;Thomson, E
通讯作者：
Thomson, E
DOI：
10.1152/ajpheart.1996.270.4.h1149
发表时间：
1996-04-01
影响因子：
4.8
作者：
Descamps, L;Dehouck, MP;Cecchelli, R
通讯作者：
Cecchelli, R
影响因子：
8.4
作者：
Hirayama, Tasuku;Okuda, Kensuke;Nagasawa, Hideko
通讯作者：
Nagasawa, Hideko