Protection of Retinal Function by Nucleoside Reverse Transcriptase Inhibitors Following Retinal Ischemia/Reperfusion Injury
Protection of Retinal Function by Nucleoside Reverse Transcriptase Inhibitors Following Retinal Ischemia/Reperfusion Injury
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DOI：
10.1089/jop.2020.0083
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发表时间：
2021-08-26
影响因子：
2.3
通讯作者：
Bu, Ping
中科院分区：
文献类型：
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作者：
Gange, William S.;Qiao, James B.;Bu, Ping
目的：视网膜缺血/再灌注(I/R)损伤是导致视力损害和失明的常见原因，其治疗方案仍然有限。核苷逆转录酶抑制剂(NRTI)，如齐多夫定(AZT)，已被证明可以阻断NLRP3炎症小体，并防止老年性黄斑变性小鼠的视网膜退化。NLRP3炎症体也被证明在I/R损伤中被触发。因此，我们利用压力性视网膜缺血小鼠模型研究了AZT的神经保护作用。方法：将C57BL/6J小鼠随机分为两组，每组6只，每组6只，每组6只，每组6只。生理盐水中加入1%二甲基亚砜(DMSO)或1%DMSO中加入AZT 50 mg/kg，每日2次，连续5d。治疗第2天，通过一过性高眼压45min诱导视网膜缺血。在视网膜缺血损伤前和损伤后1周分别进行暗视视网膜电流图(ERG)检测。于缺血损伤后1周观察视网膜形态变化。视网膜I/R损伤后24 h进行末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)检测和caspase 1免疫组织化学染色。结果：I/R损伤后，赋形剂治疗组小鼠ERGa、b波波幅显著降低。与赋形剂处理的小鼠相比，AZT治疗显著减轻了I/R引起的视网膜功能丧失。此外，与赋形剂治疗的小鼠相比，AZT治疗的小鼠经历的视网膜内层变薄明显较少。与AZT处理的I/R损伤小鼠视网膜相比，赋形剂处理的I/R损伤小鼠视网膜中TUNEL阳性细胞较多。缺血再灌注损伤组神经节细胞层和内核层的caspase-1免疫反应阳性细胞数明显多于AZT治疗组。结论：与对照组相比，AZT治疗可以相对保护缺血损伤后视网膜的结构和功能。提示AZT在视网膜缺血性疾病的治疗中可能具有一定的治疗价值。
Purpose: Retinal ischemia/reperfusion (I/R) injury is a common cause of visual impairment and blindness for which there remain limited treatment options. Nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (AZT), have been shown to block the NLRP3 inflammasome and prevent retinal degeneration in a mouse model of age-related macular degeneration. The NLRP3 inflammasome has also been shown to be triggered in I/R injury. Therefore, we studied the neuroprotective effects of AZT using a pressure-induced retinal ischemia mouse model. Methods: C57BL/6J mice were randomly assigned to 1 of 2 treatment groups: vehicle-treated retinal I/R injury (n = 6) or AZT-treated retinal I/R injury (n = 6). Vehicle (1% dimethyl sulfoxide [DMSO] in phosphate-buffered saline [PBS]) or AZT 50 mg/kg in 1% DMSO in PBS were injected intraperitoneally twice daily for 5 days. On day 2 of treatment, retinal ischemia was induced by transient elevation of intraocular pressure for 45 min. Scotopic electroretinography (ERG) was used to quantify retinal function before and 1 week after retinal ischemic insult. Retinal morphology was examined 1 week after ischemic insult. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and caspase 1 immunostaining was performed 24 h after retinal I/R injury. Results: Following I/R injury, ERG a- and b-wave amplitudes were significantly reduced in the vehicle-treated mice. AZT treatment significantly attenuated I/R-induced loss of retinal function as compared with vehicle-treated mice. Additionally, AZT-treated mice experienced significantly less inner retinal thinning as compared with vehicle-treated mice. TUNEL-positive cells were prevalent in the vehicle-treated I/R injury mouse retinas compared with the AZT-treated I/R injury mouse retinas. More caspase-1 immunoreactivity was detected in ganglion cell layer and inner nuclear layer (INL) in vehicle-treated I/R injury group than in AZT-treated I/R injury group. Conclusion: AZT treatment resulted in relative preservation of retinal structure and function following ischemic insult as compared with controls. This suggests AZT may have therapeutic value in the management of retinal ischemic diseases.