ReviewFerroptosis and traumatic brain injury
Introduction
Over 50 million people around the world experience traumatic brain injury (TBI) every year and about 50 % of the world’s population are likely to suffer at least one TBI throughout their lives (Feigin et al., 2013). TBI deserves attention due to its considerable long-term effects which include poor functional outcomes, risk of developing additional neurological diseases and increased mortality (Wilson et al., 2017). TBI results from an external physical force such as a blow, a penetration, or a blast, resulting in a range of brain pathologies that alter normal brain function (Pavlovic et al., 2019). TBI are divided into mild, moderate, or severe according to defined criteria. In addition to the primary damage caused by mechanical forces immediately after the injury, TBI can promote delayed demise of brain tissue termed secondary injury (Ng and Lee, 2019). The mechanisms of primary injury include breach of the blood-brain barrier, damage to axonal fibers, and cell death (Corps et al., 2015; Blennow et al., 2012). The mechanisms leading to secondary injury include oxidative stress, lipid peroxidation, and inflammation (Ng and Lee, 2019).
Ferroptosis is a newly discovered mode of regulated cell death resulting from fatal, iron-catalyzed lipid damage and is significantly different from other known cell death pathways (Stockwell et al., 2017). The hallmark of ferroptosis is an overwhelming production of iron-dependent reactive oxygen species (ROS) with reduced glutathione (GSH) levels and inactivation of glutathione peroxidase 4 (GPX4) (Hirschhorn and Stockwell, 2019; Yang and Stockwell, 2016). Many studies have found direct or indirect evidence for the participation of ferroptosis in the pathology of TBI. For example, a study in mice found iron accumulation and up-regulation of genes associated with ferroptosis in mice that had experienced TBI; other findings included evidence that ferroptosis inhibition ameliorated tissue damage and improved long-term outcomes (Xie et al., 2019). Similarly, another study using HT22 neuronal cells and C57BL/6 mice to build TBI models showed that ferroptosis potentially participated in the pathogenesis of both in vitro and in vivo TBI (Kenny et al., 2019).
Section snippets
Iron dysmetabolism
Iron is an important trace element in humans due to its fundamental biological functions as important components of hemoglobin and of many other enzymes. Under normal circumstances, iron exists as Fe3+ in transferrin (Tf)-iron form in neurons. The transferrin receptor (TfR) protein regulates the metabolism of the iron form, and Tf-TfR complex is responsible for the intake of iron in brain. In the endosome, low pH conditions lead to disruption of the Tf-iron-TfR complex, releasing iron and
Role of ferroptosis in the chronic phase of TBI
TBI is a chronic health condition with major long term consequences including cognitive deficits, de novo neurodegenerative diseases, post-trauma epilepsy, and psychiatric illness (Wilson et al., 2017). Ferroptosis has been shown be a major contributor of these long term outcomes.
Activation of the nuclear factor erythroid 2-related factor 2 pathway
The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) participates in the pathology after TBI through different routes, such as neuroinflammation, autophagy, and apoptosis, and the corresponding treatment has been proven to affect TBI outcomes (Chen et al., 2018; Zhang et al., 2017; Bhowmick et al., 2019). Currently, Nrf2 has received attention for its ability to regulate many genes that are directly or indirectly related to the initial development or regulation of
Conclusions
To date, none of the neuroprotective therapies for TBI patients have demonstrated clinical efficacy. It is critical to understand the complex mechanisms of TBI and its chronic sequelae. Insights into ferroptosis provides a different perspective. Ferroptosis is a novel pathophysiological pathway of TBI. The occurrence of ferroptosis after TBI is well established, but the exact role of ferroptosis in the chronic phases of TBI and remain unclear. Future studies should focus on the following
Author contributions
Zhu Wusheng: Conceptualization, Writing - Review & Editing.Geng Zhiwen: Writing - Original Draft. Guo Zhiliang, Guo Ruibing, Ye Ruidong, Bernard Yan: Writing - Review & Editing, Project administration.
Declaration of Competing Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgements
This study was supported in part by the National Natural Science Foundation of China (NO. 81671170) and Natural Science Foundation of Jiangsu Province (BK20201234).
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