Ruxolitinib exerts neuroprotection via repressing ferroptosis in a mouse model of traumatic brain injury
Ruxolitinib exerts neuroprotection via repressing ferroptosis in a mouse model of traumatic brain injury
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鲁索替尼通过抑制创伤性脑损伤小鼠模型中的铁死亡发挥神经保护作用
DOI：
10.1016/j.expneurol.2021.113762
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发表时间：
2021-05-19
影响因子：
5.3
通讯作者：
Tao, Luyang
中科院分区：
文献类型：
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作者：
Chen, Xueshi;Gao, Cheng;Tao, Luyang
外伤性脑损伤（TBI）是世界范围内造成死亡和残疾的主要原因。多种形式的细胞死亡参与了TBI的病理过程，铁凋亡也不例外，铁凋亡主要由铁依赖性脂质过氧化引起。虽然已有关于铁沉和TBI的研究，但FDA批准的一类治疗骨髓纤维化的药物ruxolitinib （Ruxo）对TBI后铁沉过程的影响尚不清楚。因此，我们采用控制性皮质撞击装置建立小鼠TBI模型，以铁沉陷抑制剂铁抑素-1 （Ferrostatin-1, Fer-1）为阳性对照，检测Ruxo对TBI诱导的铁沉陷的影响。此外，我们还分别探讨了这两种干预措施对TBI引起的神经功能障碍的影响。我们首先检测了脑外伤后不同时间点细胞凋亡相关标志物在蛋白水平上的表达模式。根据这些标志物的表达变化，我们选择tbi后12 h来证明Ruxo对铁下垂的影响。重要的是，我们发现Ruxo对铁下垂有强烈的抑制作用，这与fe -1治疗后的结果是一致的。此外，两种治疗方法均可减轻急性期脑水含量和神经退行性变程度。最后，我们分别通过抓丝实验、Morris水迷宫实验和野外实验进一步证实了Ruxo或Fer-1的神经保护作用。之后，还测量了病变体积和铁沉积，以证明它们对TBI的长期预后的影响。我们的结果最终证明抑制铁下垂具有神经保护作用，这是Ruxo对TBI的另一种神经保护机制。
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.