Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice
Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice
复制标题
抑制铁死亡可减轻小鼠脑外伤后的组织损伤并改善长期结果
DOI：
10.1111/cns.13069
复制
发表时间：
2019-04-01
影响因子：
5.5
通讯作者：
Jiang, Ji-Yao
中科院分区：
文献类型：
--
作者：
Xie, Bao-Shu;Wang, Yi-Qin;Jiang, Ji-Yao
铁凋亡是一种新形式的铁依赖性程序性细胞死亡，已被证明与一系列疾病有关。然而，铁下垂在创伤性脑损伤（TBI）中的作用尚未阐明。我们的目的是研究TBI后是否会诱导铁凋亡，以及抑制铁凋亡是否会在受控皮质撞击损伤（CCI）小鼠模型中保护创伤性脑损伤。方法建立小鼠TBI模型，观察TBI后铁凋亡相关的生化和形态学改变，包括Perl染色观察铁蓄积，Fluoro-Jade B（FJB）染色观察神经元细胞死亡，Western blotting观察铁代谢障碍，丙二醛（MDA）测定观察活性氧（ROS）蓄积，透射电镜观察线粒体皱缩。此外，CCI后脑室注射特异性铁凋亡抑制剂ferrostatin-1（fer-1）。我们使用甲酚紫（CV）染色来评估病变体积，沿着使用Morris水迷宫和平衡木行走试验来评估长期结果。结果TBI后出现铁蓄积、铁代谢紊乱、铁代谢相关基因表达上调、还原型谷胱甘肽过氧化物酶（GPx）活性升高和脂质活性氧（ROS）蓄积。TBI后3天，透射电子显微镜（TEM）证实线粒体萎缩，这是铁凋亡的典型特征。重要的是，通过脑室注射给予Fer-1显著减少了铁沉积和神经元变性，同时减轻了损伤病变并改善了长期运动和认知功能。结论本研究为靶向治疗TBI提供了一种有效的方法。
Aims Ferroptosis, a new form of iron-dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. Methods After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro-Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin-1(fer-1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long-term outcomes. Results TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis-related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid-reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer-1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long-term motor and cognitive function. Conclusion This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.