Ruxolitinib exerts neuroprotection via repressing ferroptosis in a mouse model of traumatic brain injury

被引:44
作者
Chen, Xueshi [1 ]
Gao, Cheng [1 ]
Yan, Ya'nan [1 ]
Cheng, Zhiqi [1 ]
Chen, Guang [1 ]
Rui, Tongyu [1 ]
Luo, Chengliang [1 ]
Gao, Yuan [1 ]
Wang, Tao [1 ]
Chen, Xiping [1 ]
Tao, Luyang [1 ]
机构
[1] Soochow Univ, Affiliated Guangji Hosp, Sch Basic Med & Biol Sci, Dept Forens Med, Suzhou, Peoples R China
关键词
Traumatic brain injury; Ferroptosis; Ruxolitinib; Neuroprotection; Lipid peroxidation; CELL-DEATH; LIPID-PEROXIDATION; COGNITIVE IMPAIRMENT; IN-VITRO; ACTIVATION; ABLATION; CYCLOOXYGENASE-2; INHIBITION; METABOLISM; PYROPTOSIS;
D O I
10.1016/j.expneurol.2021.113762
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Various forms of cells death are involved in the pathological process of TBI, without exception to ferroptosis, which is mainly triggered by irondependent lipid peroxidation. Although there have been studies on ferroptosis and TBI, the effect of ruxolitinib (Ruxo), one type of FDA approved drugs for treating myelofibrosis, on the process of ferroptosis post-TBI is remained non-elucidated. Therefore, using a controlled cortical impact device to establish the mouse TBI model, we examined the effect of Ruxo on TBI-induced ferroptosis, in which the inhibitor of ferroptosis, Ferrostatin-1 (Fer-1) was used as a positive control. Moreover, we also respectively explored the effects of these two interventions on neurological deficits caused by TBI. We firstly examined the expression patterns of ferroptosisrelated markers at protein level at different time points after TBI. And based on the expression changes of these markers, we chose 12 h post-TBI to prove the effect of Ruxo on ferroptosis. Importantly, we found the intensely inhibitory effect of Ruxo on ferroptosis, which is in parallel with the results obtained after Fer-1treatment. In addition, these two treatments both alleviated the content of brain water and degree of neurodegeneration in the acute phase of TBI. Finally, we further confirmed the neuroprotective effect of Ruxo or Fer-1 via the wire-grip test, Morris water maze and open field test, respectively. Thereafter, the lesion volume and iron deposition were also measured to certificate their effects on the long-term outcomes of TBI. Our results ultimately demonstrate that inhibiting ferroptosis exerts neuroprotection, and this is another neuroprotective mechanism of Ruxo on TBI.
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页数:10
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