Neural Circuit Development and Regeneration Research Group, Department of Biology, Zoological Institute, KU Leuven, Leuven, Belgium.
Oxurion NV, Leuven, Belgium.
Invest Ophthalmol Vis Sci. 2019 Feb 1;60(2):807-822. doi: 10.1167/iovs.18-25372.
The goal of this study was to perform an extensive temporal characterization of the early pathologic processes in the streptozotocin (STZ)-induced diabetic retinopathy (DR) mouse model, beyond the vascular phenotype, and to investigate the potential of clinically relevant compounds in attenuating these processes.
Visual acuity and contrast sensitivity (CS) were studied in the mouse STZ model until 24 weeks postdiabetes onset. ERG, spectral domain optical coherence tomography (SD-OCT), leukostasis, and immunohistochemistry were applied to investigate neurodegeneration, inflammation, and gliosis during early-, mid- and late-phase diabetes. Aflibercept or triamcinolone acetonide (TAAC) was administered to investigate their efficacy on the aforementioned processes.
Visual acuity and CS loss started at 4 and 18 weeks postdiabetes onset, respectively, and progressively declined over time. ERG amplitudes were diminished and OP latencies increased after 6 weeks, whereas SD-OCT revealed retinal thinning from 4 weeks postdiabetes. Immunohistochemical analyses linked these findings to retinal ganglion and cholinergic amacrine cell loss at 4 and 8 weeks postdiabetes onset, respectively, which was further decreased after aflibercept administration. The number of adherent leukocytes was augmented after 2 weeks, whereas increased micro- and macroglia reactivity was present from 4 weeks postdiabetes. Aflibercept or TAAC showed improved efficacy on inflammation and gliosis.
STZ-induced diabetic mice developed early pathologic DR hallmarks, from which inflammation seemed the initial trigger, leading to further development of functional and morphologic retinal changes. These findings indicate that the mouse STZ model is suitable to study novel integrative non-vascular therapies to treat early DR.
本研究的目的是对链脲佐菌素（STZ）诱导的糖尿病视网膜病变（DR）小鼠模型的早期病理过程进行广泛的时间特征描述，超越血管表型，并研究临床相关化合物在减轻这些过程中的潜力。
在糖尿病发病后 24 周之前，研究了小鼠 STZ 模型的视力和对比敏感度（CS）。应用视网膜电图（ERG）、谱域光相干断层扫描（SD-OCT）、白细胞黏附和免疫组织化学来研究早期、中期和晚期糖尿病中的神经退行性变、炎症和神经胶质增生。给予阿柏西普或曲安奈德（TAAC）以研究它们对上述过程的疗效。
视力和 CS 损失分别在糖尿病发病后 4 周和 18 周开始，并随时间逐渐下降。ERG 幅度在 6 周后降低，OP 潜伏期增加，而 SD-OCT 显示视网膜从糖尿病发病后 4 周开始变薄。免疫组织化学分析将这些发现与视网膜神经节和胆碱能无长突细胞在糖尿病发病后 4 周和 8 周的损失联系起来，在给予阿柏西普后进一步减少。黏附白细胞的数量在 2 周后增加，而微胶质和巨胶质的反应性从糖尿病发病后 4 周开始增加。阿柏西普或 TAAC 对炎症和神经胶质增生显示出更好的疗效。
STZ 诱导的糖尿病小鼠出现了早期的 DR 病理特征，其中炎症似乎是最初的触发因素，导致进一步发展为功能性和形态学的视网膜变化。这些发现表明，小鼠 STZ 模型适合研究新型综合非血管治疗方法来治疗早期 DR。
