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Investigations on Alterations of Hippocampal Circuit Function Following Mild Traumatic Brain Injury
Published on: November 19, 2012
Stress-mediated Activation of Ferroptosis, Pyroptosis, and Apoptosis Following Mild Traumatic Brain Injury
Lexin Zheng1, Qiuyu Pang1, Ruoyu Huang1
1Soochow University, Suzhou, China.
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.
Insights
Stress worsens mild traumatic brain injury (mTBI) outcomes by promoting iron-driven cell death pathways like ferroptosis. Targeting ferroptosis with iron chelators may improve recovery for mTBI patients experiencing stress.
Area of Science:
- Neuroscience
- Cell Biology
- Pathophysiology
Background:
- Mild traumatic brain injury (mTBI) often results in persistent neurological deficits.
- Stress is a significant factor influencing mTBI outcomes and recovery.
- Ferroptosis, a form of regulated cell death, is implicated in TBI pathophysiology.
Purpose of the Study:
- To investigate the impact of acute and chronic stress on mTBI-induced neurological dysfunction.
- To elucidate the role of ferroptosis in stress-exacerbated mTBI.
- To evaluate the therapeutic potential of targeting ferroptosis in stress-sensitive mTBI patients.
Main Methods:
- Established a mouse model of mild traumatic brain injury (mTBI).
- Applied acute restraint stress (RS) and chronic unpredictable mild stress (CUMS) models.
- Utilized iron chelators (deferoxamine, ciclopirox) to inhibit ferroptosis.
Main Results:
- Acute RS and CUMS exacerbated mTBI-induced neurological deficits, brain injury, and cell death (ferroptosis, pyroptosis, apoptosis).
- Stress promoted iron deposition and overload in the neocortex following mTBI.
- Inhibition of ferroptosis with iron chelators ameliorated stress-induced exacerbation of cell death and neurological dysfunction.
Conclusions:
- Stress significantly worsens mTBI outcomes by promoting iron-dependent cell death, particularly ferroptosis.
- Targeting ferroptosis via iron chelation offers a potential therapeutic strategy for mTBI patients exposed to stress.
- Understanding the interplay between stress, iron metabolism, and cell death is crucial for mTBI treatment.
