Rescue of Retinal Degeneration in rd1 Mice by Intravitreally Injected Metformin
Rescue of Retinal Degeneration in rd1 Mice by Intravitreally Injected Metformin
复制标题
玻璃体内注射二甲双胍拯救rd1小鼠视网膜变性
DOI：
10.3389/fnmol.2019.00102
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发表时间：
2019-04-26
影响因子：
4.8
通讯作者：
Xu, Haiwei
中科院分区：
文献类型：
--
作者：
Luodan, A.;Zou, Ting;Xu, Haiwei
视网膜色素变性（Retinitis pigmentosa，RP）是一种进行性遗传性视网膜变性疾病，其感光细胞发生变性和凋亡，最终导致不可逆的视功能丧失。目前，对这种疾病没有有效的治疗方法。据报道，神经保护和炎症抑制可延缓RP的发展。二甲双胍是一种用于治疗2型糖尿病的经过充分测试的药物，据报道，它对神经退行性疾病如帕金森病和阿尔茨海默病具有有益作用。本研究采用免疫荧光染色、视网膜电图（ERG）记录和RNA-Seq技术，探讨二甲双胍对rd 1小鼠视网膜光感受器变性的影响及其机制。我们发现，二甲双胍显著减少了rd 1小鼠光感受器的凋亡，并延迟了rd 1小鼠光感受器和视杆双极细胞的变性，从而在P14、P18和P22时显著改善了rd 1小鼠的视觉功能（采用亮/暗转换试验和ERG进行测试）。二甲双胍显著抑制rd 1小鼠视网膜外核层（ONL）中的小胶质细胞活化。RNA-Seq显示，二甲双胍显著下调炎症基因并上调晶状体蛋白的表达，晶状体蛋白已被证明是视网膜中重要的神经保护分子，揭示了二甲双胍治疗RP的治疗潜力。在Ca 2+离子载体损伤的661 W光感受器样细胞系中，α A-晶状体蛋白质被进一步证实参与二甲双胍的神经保护作用。这些数据表明，二甲双胍通过免疫调节和新的神经保护机制在rd 1小鼠中发挥保护作用。
Retinitis pigmentosa (RP) is a progressive hereditary retinal degenerative disease in which photoreceptor cells undergo degeneration and apoptosis, eventually resulting in irreversible loss of visual function. Currently, no effective treatment exists for this disease. Neuroprotection and inflammation suppression have been reported to delay the development of RP. Metformin is a well-tested drug used to treat type 2 diabetes, and it has been reported to exert beneficial effects in neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. In the present study, we used immunofluorescence staining, electroretinogram (ERG) recordings and RNA-Seq to explore the effects of metformin on photoreceptor degeneration and its mechanism in rd1 mice. We found that metformin significantly reduced apoptosis in photoreceptors and delayed the degeneration of photoreceptors and rod bipolar cells in rd1 mice, thus markedly improving the visual function of rd1 mice at P14, P18, and P22 when tested with a light/dark transition test and ERG. Microglial activation in the outer nuclear layer (ONL) of the retina of rd1 mice was significantly suppressed by metformin. RNA-Seq showed that metformin markedly downregulated inflammatory genes and upregulated the expression of crystallin proteins, which have been demonstrated to be important neuroprotective molecules in the retina, revealing the therapeutic potential of metformin for RP treatment. alpha A-crystallin proteins were further confirmed to be involved in the neuroprotective effects of metformin in a Ca2+ ionophore-damaged 661W photoreceptor-like cell line. These data suggest that metformin exerts a protective effect in rd1 mice via both immunoregulatory and new neuroprotective mechanisms.