Deferasirox, a trivalent iron chelator, ameliorates neuronal damage in hemorrhagic stroke models
Deferasirox, a trivalent iron chelator, ameliorates neuronal damage in hemorrhagic stroke models
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地拉罗司，一种三价铁螯合剂，改善出血性中风模型中的神经元损伤
DOI：
10.1007/s00210-020-01963-6
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发表时间：
2020-08-18
影响因子：
3.6
通讯作者：
Shimazawa, Masamitsu
中科院分区：
文献类型：
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作者：
Imai, Takahiko;Tsuji, Shohei;Shimazawa, Masamitsu
目的颅内出血（Intracranial hemorrhage，ICH）是一种致死率和致残率都很高的严重疾病.脑出血后，血肿释放的铁在继发性脑损伤中起着至关重要的作用。地拉罗司（DFR）是一种三价铁螯合剂，已被批准用于治疗输血后铁超载综合征。本研究的目的是研究DFR在体外和体内ICH模型中的保护作用。方法采用氯化血红素诱导的SH-SY 5 Y细胞损伤模型，通过细胞内二价铁（Fe 2+）积累试验、细胞死亡试验、氧化应激试验和Western blotting分析。此外，DFR脑室内给药的血肿，神经功能缺损，和组织学改变的影响进行了评估，在体内ICH小鼠模型的胶原酶。结果DFR能显著抑制氯化血红素引起的细胞内Fe（2+）蓄积和细胞死亡。这些作用与抑制活性氧和脂质过氧化反应有关。在蛋白质印迹分析中，氯化血红素增加了铁蛋白（一种铁储存蛋白）、LC 3和p62（自噬相关标志物）、磷酸化p38（一种应激反应蛋白）、切割半胱天冬酶3和切割聚（二磷酸腺苷核糖）聚合酶（PARP）（凋亡相关标志物）的表达。但DFR抑制了这些蛋白的增加。此外，DFR可减轻神经功能缺损，直至ICH后7天，而不影响血肿和损伤面积。此外，DFR还抑制了ICH后3天血肿周围区域的小胶质细胞/巨噬细胞活化。结论DFR可能是一种治疗脑出血的有效药物。
Purpose Intracranial hemorrhage (ICH) is a devastating disease with high mortality and morbidity. After ICH, iron released from the hematoma plays a crucial role in secondary brain injury. Deferasirox (DFR) is a trivalent iron chelator, which was approved to treat iron overload syndrome after transfusion. The aim of the present study was to investigate the protective effects of DFR in both in vitro and in vivo ICH models. Methods Using a hemin-induced SH-SY5Y cell damage model, we performed an intracellular bivalent iron (Fe2+) accumulation assay, cell death assay, oxidative stress assessments, and Western blotting analysis. Moreover, the effects of DFR intraventricular administration on hematoma, neurological deficits, and histological alteration were evaluated in an in vivo ICH mouse model by collagenase. Results DFR significantly suppressed the intracellular Fe(2+)accumulation and cell death caused by hemin exposure. These effects were related to the suppression of both reactive oxygen species and lipid peroxidation over-production. In Western blotting analysis, hemin increased the expression of ferritin (an iron storage protein), LC3 and p62 (autophagy-related markers), phosphorylated p38 (a stress response protein), and cleaved-caspase3 and cleaved-poly (adenosine diphosphate ribose) polymerase (PARP) (apoptosis-related makers). However, DFR suppressed the increase of these proteins. In addition, DFR attenuated the neurological deficits until 7 days after ICH without affecting hematoma and injury area. Furthermore, DFR also suppressed microglia/macrophage activation in peri-hematoma area at 3 days after ICH. Conclusion These findings indicate that DFR might be a useful therapeutic agent for the therapy of ICH.