Neuroprotection of brain-permeable iron chelator VK-28 against intracerebral hemorrhage in mice
Neuroprotection of brain-permeable iron chelator VK-28 against intracerebral hemorrhage in mice
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DOI：
10.1177/0271678x17709186
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发表时间：
2017-09-01
影响因子：
6.3
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Li, Qian;Wan, Jieru;Wang, Jian
铁过载在脑出血（ICH）后发生的继发性脑损伤中起着关键作用。铁沉积的显着增加与活性氧（ROS）的产生有关，从而导致氧化性脑损伤。在这项研究中，我们在离体器官型海马切片培养 (OHSC) 模型和体内胶原酶诱导的 ICH 模型中检查了 VK-28（一种脑渗透性铁螯合剂）对血红蛋白毒性的保护作用。我们发现 VK-28 的作用与去铁胺 (DFX)（一种经过充分研究的铁螯合剂）的作用相似。两者都减少了 OHSC 和体内的细胞死亡和 ROS 产生，减少了体内血肿周围的铁沉积和小胶质细胞活化，并改善了神经功能。此外，与 DFX 相比，VK-28 将小胶质细胞极化为 M2 样表型，降低脑含水量，减少白质损伤，改善神经行为表现，并降低 ICH 后的总体死亡率。 VK-28 的保护作用在注射血液 ICH 模型以及老年雄性和年轻雌性小鼠中得到证实。我们的研究结果表明，VK-28 对 ICH 后的铁毒性具有保护作用，并且在测试剂量下，它比 DFX 具有更好的功效和更低的毒性。
Iron overload plays a key role in the secondary brain damage that develops after intracerebral hemorrhage (ICH). The significant increase in iron deposition is associated with the generation of reactive oxygen species (ROS), which leads to oxidative brain damage. In this study, we examined the protective effects of VK-28, a brain-permeable iron chelator, against hemoglobin toxicity in an ex vivo organotypic hippocampal slice culture (OHSC) model and in middle-aged mice subjected to an in vivo, collagenase-induced ICH model. We found that the effects of VK-28 were similar to those of deferoxamine (DFX), a well-studied iron chelator. Both decreased cell death and ROS production in OHSCs and in vivo, decreased iron-deposition and microglial activation around hematoma in vivo, and improved neurologic function. Moreover, compared with DFX, VK-28 polarized microglia to an M2-like phenotype, reduced brain water content, deceased white matter injury, improved neurobehavioral performance, and reduced overall death rate after ICH. The protection of VK-28 was confirmed in a blood-injection ICH model and in aged-male and young female mice. Our findings indicate that VK-28 is protective against iron toxicity after ICH and that, at the dosage tested, it has better efficacy and less toxicity than DFX does.