阿昔洛韦的一种临床代谢物抑制实验性脉络膜新生血管和视网膜色素上皮变性。
A Clinical Metabolite of Azidothymidine Inhibits Experimental Choroidal Neovascularization and Retinal Pigmented Epithelium Degeneration.
机构信息
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出版信息
Invest Ophthalmol Vis Sci. 2020 Aug 3;61(10):4. doi: 10.1167/iovs.61.10.4.
PURPOSE
Azidothymidine (AZT), a nucleoside reverse transcriptase inhibitor, possesses anti-inflammatory and anti-angiogenic activity independent of its ability to inhibit reverse transcriptase. The aim of this study was to evaluate the efficacy of 5'-glucuronyl azidothymidine (GAZT), an antiretrovirally inert hepatic clinical metabolite of AZT, in mouse models of retinal pigment epithelium (RPE) degeneration and choroidal neovascularization (CNV), hallmark features of dry and wet age-related macular degeneration (AMD), respectively.
METHODS
RPE degeneration was induced in wild-type (WT) C57BL/6J mice by subretinal injection of Alu RNA. RPE degeneration was assessed by fundus photography and confocal microscopy of zonula occludens-1-stained RPE flat mounts. Choroidal neovascularization was induced by laser injury in WT mice, and CNV volume was measured by confocal microscopy. AZT and GAZT were delivered by intravitreous injections. Inflammasome activation was monitored by western blotting for caspase-1 and by ELISA for IL-1β in Alu RNA-treated bone marrow-derived macrophages (BMDMs).
RESULTS
GAZT inhibited Alu RNA-induced RPE degeneration and laser-induced CNV. GAZT also reduced Alu RNA-induced caspase-1 activation and IL-1β release in BMDMs.
CONCLUSIONS
GAZT possesses dual anti-inflammatory and anti-angiogenic properties and could be a viable treatment option for both forms of AMD.
目的
叠氮胸苷（AZT）是一种核苷逆转录酶抑制剂，具有抗炎和抗血管生成活性，而不依赖其抑制逆转录酶的能力。本研究旨在评估 AZT 的肝内临床代谢物 5'-葡糖醛酸叠氮胸苷（GAZT）在视网膜色素上皮（RPE）变性和脉络膜新生血管（CNV）小鼠模型中的疗效，这分别是干性和湿性年龄相关性黄斑变性（AMD）的标志性特征。
方法
通过视网膜下注射 Alu RNA 在野生型（WT）C57BL/6J 小鼠中诱导 RPE 变性。通过巩膜摄影和封闭蛋白-1 染色的 RPE 平片的共聚焦显微镜评估 RPE 变性。通过激光损伤在 WT 小鼠中诱导脉络膜新生血管，通过共聚焦显微镜测量 CNV 体积。通过玻璃体内注射给予 AZT 和 GAZT。通过 Western blot 监测 Alu RNA 处理的骨髓来源巨噬细胞（BMDMs）中半胱天冬酶-1 的激活，通过 ELISA 监测 IL-1β的释放来监测炎症小体的激活。
结果
GAZT 抑制 Alu RNA 诱导的 RPE 变性和激光诱导的 CNV。GAZT 还降低了 Alu RNA 诱导的 BMDMs 中半胱天冬酶-1 的激活和 IL-1β的释放。
结论
GAZT 具有双重抗炎和抗血管生成特性，可能是两种形式 AMD 的可行治疗选择。
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