Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma
Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma
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DOI：
10.1167/iovs.17-23276
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发表时间：
2018-04-01
影响因子：
4.4
通讯作者：
Harada, Takayuki
中科院分区：
文献类型：
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作者：
Akaiwa, Kei;Namekata, Kazuhiko;Harada, Takayuki
目的。为了评估利帕舒地尔是否具有神经保护作用，我们使用兴奋性氨基酸载体1 （EAAC1）缺失小鼠（EAAC1敲除[KO]小鼠）作为正常紧张性青光眼小鼠模型。5 ~ 12周龄EAAC1 KO小鼠局部给予两种不同浓度（0.4%和2%）的利帕舒地尔（5 l /天）。分别在5、8和12周大时进行光学相干断层扫描、多焦视网膜电图、眼压测量和组织病理学分析。在8周龄时对视网膜神经节细胞（RGCs）进行逆行标记、免疫印迹和磷酸化p38丝裂原活化蛋白激酶（MAPK）的免疫组织化学分析。局部利帕舒地尔改善了EAAC1 KO小鼠8周和12周时的视网膜变性和视觉功能。利帕舒地尔降低IOP，并强烈抑制p38 MAPK磷酸化，刺激EAAC1 KO小鼠RGC死亡。这些结果表明，除了降低IOP外，利帕舒地尔还通过抑制细胞死亡信号通路的神经保护作用来预防青光眼视网膜变性。
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 lL/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 celldeath signaling pathways.