Institute of Translational and Precision Medicine, Nantong University, Nantong, JS, China; Laboratory of Neuropharmacology of Pharmacy School, and National Clinical Research Center for Aging and Medicine of Huashan Hospital, Fudan University, Shanghai, China; Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei, China.
Laboratory of Neuropharmacology of Pharmacy School, and National Clinical Research Center for Aging and Medicine of Huashan Hospital, Fudan University, Shanghai, China; School of Biomedical Sciences and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Transl Res. 2021 Mar;229:53-68. doi: 10.1016/j.trsl.2020.09.002. Epub 2020 Sep 12.
Iron plays a key role in secondary neuronal injury after intracerebral hemorrhage (ICH), and hepcidin is able to reduce brain iron in iron-overloaded rats by down-regulating iron transport proteins including ferroportin 1 and transferrin receptor 1. These led us to hypothesize that hepcidin might reduce iron-mediated neurotoxicity by inhibiting iron accumulation in ICH brain. Here, we examined effects of Ad-hepcidin (hepcidin expression adenovirus) on the nonheme iron contents, expression of hepcidin, ferritin and iron transport proteins, neuronal cell survival, water contents in the brain and/or cerebrospinal fluid (CSF), and ICH-induced apoptosis, neurological deficit by RT-PCR, Western blot analysis, NeuN Immunofluorescence, TUNEL, Fluoro-Jade B staining, behavioral performance and Morris water-maze tests in 510 rats. We demonstrated that hepcidin could significantly suppress the ICH-induced increase in iron and ferritin in brain tissues and CSF by inhibiting expression of iron transport proteins, increase neuronal survival by attenuating ICH-induced apoptosis, reactive oxygen species, neurodegeneration and brain edema, as well as effectively improve ICH-induced behavioral and cognitive deficit in rats. The findings collectively showed that hepcidin could effectively attenuate iron-mediated secondary neuronal injury after ICH in rats. This naturally existing protein can potentially be developed into a therapeutic drug for the treatment of ICH patients.
铁在脑出血（ICH）后继发性神经元损伤中起着关键作用，hepcidin 能够通过下调铁转运蛋白（包括 ferroportin 1 和转铁蛋白受体 1）来减少铁过载大鼠的脑内铁。这使我们假设 hepcidin 可能通过抑制 ICH 脑内铁积累来减轻铁介导的神经毒性。在这里，我们通过 RT-PCR、Western blot 分析、NeuN 免疫荧光、TUNEL、Fluoro-Jade B 染色、行为表现和 Morris 水迷宫试验，在 510 只大鼠中研究了 Ad-hepcidin（hepcidin 表达腺病毒）对非血红素铁含量、hepcidin、铁蛋白和铁转运蛋白表达、神经元细胞存活、脑和/或脑脊液（CSF）含水量以及 ICH 诱导的细胞凋亡、神经功能缺损的影响。我们证明，hepcidin 可以通过抑制铁转运蛋白的表达，显著抑制 ICH 诱导的脑组织和 CSF 中铁和铁蛋白的增加，增加神经元存活，减轻 ICH 诱导的细胞凋亡、活性氧、神经退行性变和脑水肿，有效改善 ICH 诱导的大鼠行为和认知功能障碍。这些发现表明，hepcidin 可以有效减轻大鼠 ICH 后铁介导的继发性神经元损伤。这种天然存在的蛋白质可能有潜力开发成为治疗 ICH 患者的治疗药物。
