Eye and Vision Science Laboratory, University of Louisville School of Medicine, Louisville, Kentucky; Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky.
Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky; Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, Kentucky.
Am J Pathol. 2021 May;191(5):947-964. doi: 10.1016/j.ajpath.2021.01.016. Epub 2021 Feb 26.
This study investigated the effects of long-term NF-κB inhibition in mitigating retinal vasculopathy in a type 1 diabetic mouse model (Akita, Ins2). Akita and wild-type (C57BL/6J) male mice, 24 to 26 weeks old, were treated with or without a selective inhibitor of NF-κB, 4-methyl-N1-(3-phenyl-propyl) benzene-1,2-diamine (JSH-23), for 4 weeks. Treatment was given when the mice were at least 24 weeks old. Metabolic parameters, key inflammatory mediators, blood-retinal barrier junction molecules, retinal structure, and function were measured. JSH-23 significantly lowered basal glucose levels and intraocular pressure in Akita. It also mitigated vascular remodeling and microaneurysms significantly. Optical coherence tomography of untreated Akita showed thinning of retinal layers; however, treatment with JSH-23 could prevent it. Electroretinogram demonstrated that A- and B-waves in Akita were significantly smaller than in wild type mice, indicating that JSH-23 intervention prevented loss of retinal function. Protein levels and gene expression of key inflammatory mediators, such as NOD-like receptor family pyrin domain-containing 3, intercellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2, were decreased after JSH-23 treatment. At the same time, connexin-43 and occludin were maintained. Vision-guided behavior also improved significantly. The results show that reducing inflammation could protect the diabetic retina and its vasculature. Findings appear to have broader implications in treating not only ocular conditions but also other vasculopathies.
这项研究调查了长期 NF-κB 抑制在减轻 1 型糖尿病小鼠模型（Akita，Ins2）视网膜血管病变中的作用。24 至 26 周龄的 Akita 和野生型（C57BL/6J）雄性小鼠接受或不接受 NF-κB 的选择性抑制剂 4-甲基-N1-（3-苯基-丙基）苯-1,2-二胺（JSH-23）治疗 4 周。当小鼠至少 24 周龄时开始治疗。测量代谢参数、关键炎症介质、血视网膜屏障连接分子、视网膜结构和功能。JSH-23 可显著降低 Akita 的基础血糖水平和眼内压。它还显著减轻血管重塑和微动脉瘤。未经治疗的 Akita 的光学相干断层扫描显示视网膜层变薄；然而，JSH-23 的治疗可以预防这种情况。视网膜电图表明，Akita 的 A 和 B 波明显小于野生型小鼠，表明 JSH-23 干预可防止视网膜功能丧失。关键炎症介质（如 NOD 样受体家族吡喃结构域包含 3、细胞间黏附分子-1、诱导型一氧化氮合酶和环氧化酶-2）的蛋白水平和基因表达在 JSH-23 治疗后降低。同时，连接蛋白 43 和紧密连接蛋白保持不变。视觉引导行为也显著改善。结果表明，减少炎症可以保护糖尿病视网膜及其血管。这些发现似乎不仅在治疗眼部疾病，而且在治疗其他血管病变方面具有更广泛的意义。
