Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States.
Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus, Ohio, United States.
Invest Ophthalmol Vis Sci. 2019 Jan 2;60(1):349-357. doi: 10.1167/iovs.18-25405.
Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling is neuroprotective in some retinal damage models but its role in neuronal survival during retinal detachment (RD) is unclear. In addition, serous RDs are a prevalent side effect of MEK inhibitors (MEKi), blocking MAPK/ERK signaling for treatment of certain cancers. We tested the hypothesis that MEKi treatment in experimental RD would increase photoreceptor death.
The MEKi selumetinib was delivered daily to C57BL/6 mice at a clinically relevant dose (10 mg/mL) starting 1 day prior to creating RD with subretinal hyaluronic acid injection. Photoreceptor TUNEL and outer nuclear layer (ONL) thickness were analyzed. Phospho-ERK1/2 (pERK) distribution, glial fibrillary acidic protein (GFAP) accumulation, and Iba-1 (microglia/macrophages) were evaluated with immunofluorescence.
pERK accumulated in the Müller glia in detached retinas, but this was effectively blocked by selumetinib. Selumetinib did not induce serous RDs at day 1 and did not increase TUNEL positive photoreceptors or further decrease ONL thickness compared to controls. Retinal gliosis was not altered, but selumetinib did block the increase in intraretinal microglia/macrophage Iba-1 fluorescence intensity and acquisition of amoeboid morphology.
MAPK/ERK is neuroprotective in some retinal damage models; in RD, selumetinib blocked Müller pERK accumulation and changed the retinal microglia/macrophage phenotype but did not alter photoreceptor survival. This is consistent with the relatively good visual acuity seen in patients developing transient retinal detachments on MEK inhibitor therapy. Compensation by other neuroprotective pathways in the retina during retinal detachment may occur in the presence of MEK inhibition.
丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）信号在一些视网膜损伤模型中具有神经保护作用，但在视网膜脱离（RD）期间神经元存活中的作用尚不清楚。此外，浆液性 RD 是 MEK 抑制剂（MEKi）的常见副作用，用于治疗某些癌症时会阻断 MAPK/ERK 信号。我们检验了这样一个假设，即在实验性 RD 中使用 MEKi 治疗会增加光感受器细胞死亡。
用临床相关剂量（10 mg/mL）的 MEKi 司美替尼（selumetinib）对 C57BL/6 小鼠进行每日给药，在通过视网膜下透明质酸注射建立 RD 前 1 天开始给药。分析光感受器细胞 TUNEL 及外核层（ONL）厚度。用免疫荧光法评估磷酸化 ERK1/2（pERK）分布、胶质纤维酸性蛋白（GFAP）积累和 Iba-1（小胶质细胞/巨噬细胞）。
脱离的视网膜中 Müller 胶质细胞中 pERK 积累，但这被司美替尼有效阻断。司美替尼在第 1 天没有诱导浆液性 RD，与对照组相比，也没有增加 TUNEL 阳性光感受器细胞或进一步减少 ONL 厚度。视网膜神经胶质增生没有改变，但司美替尼阻断了视网膜内小胶质细胞/巨噬细胞 Iba-1 荧光强度的增加和阿米巴样形态的获得。
在某些视网膜损伤模型中，MAPK/ERK 具有神经保护作用；在 RD 中，司美替尼阻断 Müller 细胞 pERK 积累并改变视网膜小胶质细胞/巨噬细胞表型，但不改变光感受器细胞的存活。这与 MEK 抑制剂治疗中发生短暂性视网膜脱离的患者相对较好的视力相吻合。在存在 MEK 抑制的情况下，视网膜可能通过其他神经保护途径进行代偿。
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