局部应用利帕舒地尔抑制正常眼压青光眼小鼠模型中的视网膜神经节细胞死亡。

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma.

机构信息

Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

出版信息

Invest Ophthalmol Vis Sci. 2018 Apr 1;59(5):2080-2089. doi: 10.1167/iovs.17-23276.

DOI:10.1167/iovs.17-23276

PMID:29677370

Abstract

PURPOSE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

摘要

目的

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。

方法

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。