Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

CNS Neuroscience and Therapeutics - Tập 25 Số 4 - Trang 465-475 - 2019
Baoshu Xie1,2, Yi‐Qin Wang3, Yong Lin1,2, Qing Mao1, Junfeng Feng1,2, Guoyi Gao1,2, Jiyao Jiang1,2
1Department of Neurosurgery School of Medicine Ren Ji Hospital Shanghai Jiao Tong University Shanghai China
2Shanghai Institute of Head Trauma, Shanghai, China
3Sino-French Research Center for Life Sciences and Genomics State Key Laboratory of Medical Genomics Rui-Jin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

Tóm tắt

SummaryAimsFerroptosis, 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.MethodsAfter 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.ResultsTBI 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.ConclusionThis study demonstrated an effective method with which to treat TBI by targeting ferroptosis.

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Tài liệu tham khảo

Brazinova A, 2016, Epidemiology of traumatic brain injury in europe: a living systematic review, J Neurotrauma, 33, 1

10.1371/journal.pmed.1002331

10.1097/MD.0000000000005342

10.1016/j.nurx.2006.01.006

10.1016/j.nec.2016.06.002

10.1016/j.bbi.2010.10.017

10.1038/srep24547

10.1089/neu.2008.0670

10.1038/jcbfm.2013.236

10.1016/j.cell.2012.03.042

Lachaier E, 2014, Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors, Anticancer Res, 34, 6417

Li Q, 2017, Inhibition of neuronal ferroptosis protects hemorrhagic brain.JCI, Insight, 2, e90777

10.1038/mp.2017.171

10.1681/ASN.2015121376

10.1016/j.cell.2017.09.021

10.1038/nchembio.2239

10.1039/C7CP00804J

10.1161/STROKEAHA.116.015609

Wenzel SE, 2017, PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals, Cell, 171, e26

10.1038/srep37063

10.1186/s12974-016-0544-4

10.1016/j.nbd.2016.05.011

10.1038/jcbfm.2010.209

10.1002/acn3.54

10.1016/j.biomaterials.2015.08.010

10.1089/neu.1998.15.599

10.1038/cdd.2015.132

10.1371/journal.pone.0011383

10.1158/0008-5472.CAN-16-1979

10.1007/s00018-017-2547-4

10.15252/embr.201744228

10.1016/j.neuint.2017.01.004

10.1155/2015/470676

10.1016/j.molcel.2015.06.011

10.1038/cddis.2016.208

10.1016/j.cell.2013.12.010

10.1038/ncb3064

Imai H, 2017, Lipid peroxidation‐dependent cell death regulated by GPx4 and ferroptosis, Curr Top Microbiol Immunol, 403, 143

10.1089/ars.2017.7115

10.1186/s12868-016-0251-1

10.1089/neu.2014.3649

10.1021/ja411006a

10.1016/j.freeradbiomed.2013.01.026

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CNS Neuroscience and Therapeutics

Tập 25 Số 4

465-475

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