Stress-mediated Activation of Ferroptosis, Pyroptosis, and Apoptosis Following Mild Traumatic Brain Injury Exacerbates Neurological Dysfunctions
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Author(s)
Zheng, Lexin
Pang, Qiuyu
Huang, Ruoyu
Xu, Heng
Guo, Hanmu
Gao, Cheng
Chen, Xueshi
Wang, Ying
Cao, Qun
Gao, Yuan
Date Issued
October 10, 2024
Journal
Molecular Neurobiology
Publisher
Springer US
Citation
Zheng, L., Pang, Q., Huang, R. et al. Stress-mediated Activation of Ferroptosis, Pyroptosis, and Apoptosis Following Mild Traumatic Brain Injury Exacerbates Neurological Dysfunctions. Mol Neurobiol 62, 4055–4075 (2025).
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Author's final manuscript
Abstract
Nearly half of mild traumatic brain injury (mTBI) patients continue to experience residual neurological dysfunction, which may be attributed to exposure to stress. Ferroptosis, a newly discovered form of cell death, is increasingly recognized for its involvement in the pathophysiology of TBI. Understanding the mechanisms by which stress influences mTBI, particularly through ferroptosis, is crucial for the effective treatment and prevention of mTBI patients who are sensitive to stressful events. In our study, a mouse mTBI model was established. An acute restraint stress (RS) and a chronic unpredictable mild stress (CUMS) model then were applied to make acute and chronic stress, respectively. We found acute RS significantly delayed the recovery of reduced body weight and short-term motor dysfunctions and exacerbated cell insults and blood–brain barrier leakage caused by mTBI. Further studies revealed that acute RS exacerbates neuronal ferroptosis, pyroptosis, and apoptosis by promoting iron overloading in the neocortex following mTBI. Interestingly, the inhibition of ferroptosis with iron chelators, including deferoxamine and ciclopirox, reversed pyroptosis and apoptosis. Moreover, CUMS aggravated neurological dysfunctions (motor function, cognitive function, and anxiety-like behavior) and exacerbated brain lesion volume. CUMS also exacerbates ferroptosis, pyroptosis, and apoptosis by intensifying iron deposition, along with decreasing the expression of neuronal brain-derived neurotrophic factor and glucocorticoid receptor in the neocortex post mTBI. These effects were also mitigated by iron chelators. Our findings suggest that alleviating ferroptosis induced by iron deposition may represent a promising therapeutic approach for mTBI patients who have experienced stressful events.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1007/s12035-024-04516-7
