Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Invest Ophthalmol Vis Sci. 2018 Apr 1;59(5):2080-2089. doi: 10.1167/iovs.17-23276.
To assess if ripasudil has a neuroprotective effect using mice with excitatory amino acid carrier 1 (EAAC1) deletion (EAAC1 knockout [KO] mice), a mouse model of normal tension glaucoma.
Topical administration (5 μL/day) of two different concentrations of ripasudil (0.4% and 2%) were applied to EAAC1 KO mice from 5 to 12 weeks old. Optical coherence tomography, multifocal electroretinograms, the measurement of intraocular pressure (IOP), and histopathology analyses were performed at 5, 8, and 12 weeks old. Retrograde labeling of retinal ganglion cells (RGCs), immunoblot, and immunohistochemical analyses of phosphorylated p38 mitogen-activated protein kinase (MAPK) in the retina were performed at 8 weeks old.
Topical ripasudil ameliorated retinal degeneration and improved visual function in EAAC1 KO mice at both 8 and 12 weeks old. Ripasudil reduced IOP and strongly suppressed the phosphorylation of p38 MAPK that stimulates RGC death in EAAC1 KO mice.
These results suggest that, in addition to IOP reduction, ripasudil prevents glaucomatous retinal degeneration by neuroprotection, which is achieved by suppressing cell-death signaling pathways.
使用兴奋性氨基酸载体 1（EAAC1）缺失（EAAC1 敲除[KO]小鼠）的小鼠评估 ripasudil 是否具有神经保护作用，EAAC1 KO 小鼠是正常眼压型青光眼的小鼠模型。
从 5 至 12 周龄起，将两种不同浓度的 ripasudil（0.4%和 2%）局部应用于 EAAC1 KO 小鼠（每天 5 μL）。在 5、8 和 12 周龄时进行光学相干断层扫描、多焦视网膜电图、眼压（IOP）测量和组织病理学分析。在 8 周龄时进行视网膜神经节细胞（RGC）逆行标记、免疫印迹和视网膜磷酸化 p38 丝裂原活化蛋白激酶（MAPK）的免疫组织化学分析。
局部使用 ripasudil 可改善 EAAC1 KO 小鼠在 8 周和 12 周龄时的视网膜变性和视觉功能。Ripasudil 降低了 IOP，并强烈抑制了 EAAC1 KO 小鼠中刺激 RGC 死亡的 p38 MAPK 的磷酸化。
这些结果表明，除了降低 IOP 外，Ripasudil 通过抑制细胞死亡信号通路来预防青光眼性视网膜变性，从而实现神经保护作用。
