Zheng Lexin, Pang Qiuyu, Huang Ruoyu, Xu Heng, Guo Hanmu, Gao Cheng, Chen Xueshi, Wang Ying, Cao Qun, Gao Yuan, Gu Zhiya, Wang Zufeng, Luo Chengliang, Tao Luyang, Wang Tao
Soochow University, Suzhou, China.
Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Mol Neurobiol. 2025 Apr;62(4):4055-4075. doi: 10.1007/s12035-024-04516-7. Epub 2024 Oct 10.
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.
近一半的轻度创伤性脑损伤（mTBI）患者持续存在残余神经功能障碍，这可能归因于应激暴露。铁死亡是一种新发现的细胞死亡形式，因其参与TBI的病理生理学过程而越来越受到认可。了解应激影响mTBI的机制，尤其是通过铁死亡的机制，对于有效治疗和预防对压力事件敏感的mTBI患者至关重要。在我们的研究中，建立了小鼠mTBI模型。然后分别应用急性束缚应激（RS）和慢性不可预测轻度应激（CUMS）模型来制造急性和慢性应激。我们发现急性RS显著延迟了体重减轻和短期运动功能障碍的恢复，并加剧了mTBI引起的细胞损伤和血脑屏障渗漏。进一步的研究表明，急性RS通过促进mTBI后新皮质中铁过载，加剧神经元铁死亡、焦亡和凋亡。有趣的是，用铁螯合剂（包括去铁胺和环吡酮）抑制铁死亡可逆转焦亡和凋亡。此外，CUMS加重了神经功能障碍（运动功能、认知功能和焦虑样行为），并加剧了脑损伤体积。CUMS还通过强化铁沉积，以及降低mTBI后新皮质中神经元脑源性神经营养因子和糖皮质激素受体的表达，加剧铁死亡、焦亡和凋亡。这些作用也被铁螯合剂减轻。我们的研究结果表明，减轻铁沉积诱导的铁死亡可能是经历过压力事件的mTBI患者一种有前景的治疗方法。
