Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
Department of Neurosurgery, School of Medicine, Gifu University, Gifu, 501-1194, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2021 Jan;394(1):73-84. doi: 10.1007/s00210-020-01963-6. Epub 2020 Aug 18.
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.
Using a hemin-induced SH-SY5Y cell damage model, we performed an intracellular bivalent iron (Fe) 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.
DFR significantly suppressed the intracellular Fe 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.
These findings indicate that DFR might be a useful therapeutic agent for the therapy of ICH.
脑出血（ICH）是一种死亡率和发病率都很高的破坏性疾病。ICH 后，血肿中释放的铁在继发性脑损伤中起关键作用。地拉罗司（DFR）是一种三价铁螯合剂，被批准用于输血后铁过载综合征的治疗。本研究旨在探讨 DFR 在体外和体内 ICH 模型中的保护作用。
使用血红素诱导的 SH-SY5Y 细胞损伤模型，我们进行了细胞内二价铁（Fe）积累测定、细胞死亡测定、氧化应激评估和 Western blot 分析。此外，通过胶原酶评估 DFR 脑室给药对脑出血小鼠模型血肿、神经功能缺损和组织学改变的影响。
DFR 显著抑制血红素暴露引起的细胞内 Fe 积累和细胞死亡。这些作用与抑制活性氧和脂质过氧化产物的产生有关。Western blot 分析显示，血红素增加了铁蛋白（一种铁储存蛋白）、LC3 和 p62（自噬相关标志物）、磷酸化 p38（应激反应蛋白）以及 cleaved-caspase3 和 cleaved-poly（腺苷二磷酸核糖）聚合酶（PARP）（凋亡相关标志物）的表达。然而，DFR 抑制了这些蛋白的增加。此外，DFR 减轻了 ICH 后 7 天内的神经功能缺损，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。
这些发现表明 DFR 可能是治疗 ICH 的一种有用的治疗剂。
