F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania Department of Ophthalmology, Second Hospital of Jilin University, Changchun, China.
Invest Ophthalmol Vis Sci. 2014 Jun 26;55(7):4525-32. doi: 10.1167/iovs.14-14568.
To investigate the retinal-protective effects of the oral iron chelator deferiprone (DFP) in mice lacking the iron regulatory hormone hepcidin (Hepc). These Hepc knockout (KO) mice have age-dependent systemic and retinal iron accumulation leading to retinal degeneration.
Hepc KO mice were given DFP in drinking water from age 6 to 18 months. They were then compared to Hepc KO mice not receiving DFP by fundus imaging, electroretinography (ERG), histology, immunofluorescence, and quantitative PCR to investigate the protective effect of DFP against retinal and retinal pigment epithelial (RPE) degeneration.
In Hepc KO mice, DFP diminished RPE depigmentation and autofluorescence on fundus imaging. Autofluorescence in the RPE layer in cryosections was significantly diminished by DFP, consistent with the fundus images. Immunolabeling with L-ferritin and transferrin receptor antibodies showed a decreased signal for L-ferritin in the inner retina and RPE cells and an increased signal for transferrin receptor in the inner retina, indicating diminished retinal iron levels with DFP treatment. Plastic sections showed that photoreceptor and RPE cells were well preserved in Hepc KO mice treated with DFP. Consistent with photoreceptor protection, the mRNA level of rhodopsin was significantly higher in retinas treated with DFP. The mRNA levels of oxidative stress-related genes heme oxygenase-1 and catalase were significantly lower in DFP-treated Hepc KO retinas. Finally, ERG rod a- and b- and cone b-wave amplitudes were significantly higher in DFP-treated mice.
Long-term treatment with the oral iron chelator DFP diminished retinal and RPE iron levels and oxidative stress, providing significant protection against retinal degeneration caused by chronic systemic iron overload in Hepc KO mice. This indicates that iron chelation could be a long-term preventive treatment for retinal disease involving iron overload and oxidative stress.
研究口服铁螯合剂地拉罗司（DFP）对缺乏铁调节激素hepcidin（Hepc）的小鼠的视网膜保护作用。这些 Hepc 基因敲除（KO）小鼠存在年龄依赖性的全身和视网膜铁蓄积，导致视网膜变性。
从 6 月龄到 18 月龄，Hepc KO 小鼠通过眼底成像、视网膜电图（ERG）、组织学、免疫荧光和定量 PCR 等方法，将接受 DFP 治疗和未接受 DFP 治疗的 Hepc KO 小鼠进行比较，以研究 DFP 对视网膜和视网膜色素上皮（RPE）变性的保护作用。
在 Hepc KO 小鼠中，DFP 减少了眼底成像中 RPE 脱色素和自发荧光。DFP 显著减少了 RPE 层的自发荧光，与眼底图像一致。用 L-铁蛋白和转铁蛋白受体抗体进行免疫标记显示，内视网膜和 RPE 细胞中的 L-铁蛋白信号减少，内视网膜中的转铁蛋白受体信号增加，表明 DFP 治疗可降低视网膜铁水平。塑料切片显示，DFP 治疗的 Hepc KO 小鼠中，光感受器和 RPE 细胞得到了很好的保存。与光感受器保护一致，DFP 处理的视网膜中的视紫红质 mRNA 水平显著升高。DFP 处理的 Hepc KO 视网膜中的氧化应激相关基因血红素加氧酶-1 和过氧化氢酶的 mRNA 水平显著降低。最后，DFP 处理的小鼠的 ERG 棒 a-和 b-波以及锥体细胞 b-波幅度显著升高。
长期口服铁螯合剂 DFP 可降低视网膜和 RPE 的铁水平和氧化应激，为 Hepc KO 小鼠慢性全身铁过载引起的视网膜变性提供显著保护。这表明铁螯合可能是一种长期的预防治疗方法，可用于涉及铁过载和氧化应激的视网膜疾病。
