Ferristatin II, an Iron Uptake Inhibitor, Exerts Neuroprotection against Traumatic Brain Injury via Suppressing Ferroptosis
Ferristatin II, an Iron Uptake Inhibitor, Exerts Neuroprotection against Traumatic Brain Injury via Suppressing Ferroptosis
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DOI：
10.1021/acschemneuro.1c00819
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发表时间：
2022-03-02
影响因子：
5
通讯作者：
Luo, Chengliang
中科院分区：
文献类型：
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作者：
Cheng, Ying;Qu, Wenhao;Luo, Chengliang
转铁蛋白受体1（transferrin receptor 1，TfR1）作为一种特异性的铁凋亡标志物，在创伤性脑损伤（traumatic brain injury，TBI）后表达增加，但TfR1在TBI诱导的铁凋亡和神经退行性变中的确切作用仍有待确定。为了进一步确定更有效的铁凋亡抑制剂和治疗TBI的有效靶点，我们的研究旨在使用铁蛋白抑制素II（铁摄取和TfR1抑制剂）在小鼠TBI模型中研究TfR1对铁凋亡的影响。铁蛋白抑制素H的作用首先在体外HT-22细胞系中得到验证，当暴露于柠檬酸铁（FAC）时显示出抗铁凋亡作用，这与从阳性对照（包括去铁胺（DFO）和利司他汀-1（Lip-1））中获得的结果平行。在体内，铁蛋白抑制素II管理TBI后12小时TfR1的表达减少，免疫荧光实验进一步证实，这种减少TfR1阳性细胞的神经元。重要的是，铁蛋白抑制素II抑制TBI诱导的铁稳态失衡，通过降低铁（III）和铁阳性沉积物的含量，并逆转铁稳态相关蛋白的表达。此外，铁蛋白抑制素II衰减TBI诱导的脂质过氧化反应，通过逆转脂质过氧化基因和蛋白质的表达，以及增加丙二醛（MDA）水平TBI。最后，铁蛋白抑制素II减轻TBI诱导的神经元损伤和神经变性，如通过用Nissl和Fluoro-Jade B染色所检测到的，从而发挥神经保护作用。总之，这些数据表明，铁蛋白抑制素II可能是一个潜在的策略，以抑制铁凋亡和开发新的治疗药物对TBI。
As a specific ferroptosis marker, transferrin receptor 1 (TfR1) expression is increased following traumatic brain injury (TBI), but the precise role of TfR1 in TBI-induced ferroptosis and neurodegeneration remains to be determined. To further identify more potent ferroptosis inhibitors and effective targets for treating TBI, our study aims at investigating the effects of TfR1 on ferroptosis in a mouse TBI model using ferristatin II (an iron uptake and TfR1 inhibitor). The effect of ferristatin H was first verified in the HT-22 cell line in vitro and showed antiferroptotic action when exposed to ferric citrate (FAC), which is in parallel with the results obtained from the positive controls, including deferoxamine (DFO) and liproxstatin-1 (Lip-1). In vivo, ferristatin II administration reduced the expression of TfR1 at 12 h after TBI, and immunofluorescence experiments further confirmed that this decreased TfR1- positive cells were neurons. Importantly, ferristatin II suppressed TBI-induced iron homeostatic imbalance by decreasing the content of Fe (III) and iron-positive deposits and reversed the expression of iron homeostasis-related proteins. Moreover, ferristatin II attenuated TBI-induced lipid peroxidation by reversing the expression of lipid peroxidative genes and proteins, as well as the increase in malondialdehyde (MDA) level following TBI. Finally, ferristatin II alleviated TBI-induced neuronal injury and neurodegeneration, as detected by staining with Nissl and Fluoro-Jade B, thereby exerting a neuroprotective effect. In summary, these data indicated that ferristatin II might be a potential strategy to restrain ferroptosis and develop novel therapeutic agents against TBI.