Daniel Abraham, Premilovac Dino, Foa Lisa, Feng Zikai, Shah Krupali, Zhang Qianyi, Woolley Krystel L, Bye Nicole, Smith Jason A, Gueven Nuri
School of Pharmacy and Pharmacology, University of Tasmania, Hobart, TAS 7005, Australia.
Tasmanian School of Medicine, University of Tasmania, Hobart, TAS 7005, Australia.
Int J Mol Sci. 2021 Jan 20;22(3):1016. doi: 10.3390/ijms22031016.
Diabetic retinopathy (DR), one of the leading causes of blindness, is mainly diagnosed based on the vascular pathology of the disease. Current treatment options largely focus on this aspect with mostly insufficient therapeutic long-term efficacy. Mounting evidence implicates mitochondrial dysfunction and oxidative stress in the central etiology of DR. Consequently, drug candidates that aim at normalizing mitochondrial function could be an attractive therapeutic approach. This study compared the mitoprotective compounds, idebenone and elamipretide, side-by-side against two novel short-chain quinones (SCQs) in a rat model of DR. The model effectively mimicked type 2 diabetes over 21 weeks. During this period, visual acuity was monitored by measuring optokinetic response (OKR). Vision loss occurred 5-8 weeks after the onset of hyperglycemia. After 10 weeks of hyperglycemia, visual function was reduced by 65%. From this point, the right eyes of the animals were topically treated once daily with the test compounds. The left, untreated eye served as an internal control. Only three weeks of topical treatment significantly restored vision from 35% to 58-80%, while visual acuity of the non-treated eyes continued to deteriorate. Interestingly, the two novel SCQs restored visual acuity better than idebenone or elamipretide. This was also reflected by protection of retinal pathology against oxidative damage, retinal ganglion cell loss, reactive gliosis, vascular leakage, and retinal thinning. Overall, mitoprotective and, in particular, SCQ-based compounds have the potential to be developed into effective and fast-acting drug candidates against DR.
糖尿病视网膜病变（DR）是导致失明的主要原因之一，主要基于该疾病的血管病理学进行诊断。目前的治疗方案大多聚焦于此，但长期治疗效果大多欠佳。越来越多的证据表明线粒体功能障碍和氧化应激在DR的核心病因中起作用。因此，旨在使线粒体功能正常化的候选药物可能是一种有吸引力的治疗方法。本研究在DR大鼠模型中，将线粒体保护化合物艾地苯醌和依拉米肽与两种新型短链醌（SCQ）进行了对比。该模型在21周内有效模拟了2型糖尿病。在此期间，通过测量视动反应（OKR）来监测视力。高血糖发作后5-8周出现视力丧失。高血糖10周后，视觉功能下降了65%。从此时起，每天对动物的右眼进行一次受试化合物局部治疗。未治疗的左眼作为内部对照。仅3周的局部治疗就使视力从35%显著恢复到58%-80%，而未治疗眼睛的视力继续恶化。有趣的是，两种新型SCQ恢复视力的效果优于艾地苯醌或依拉米肽。这也体现在对视网膜病理的保护上，包括抗氧化损伤、视网膜神经节细胞丢失、反应性胶质增生、血管渗漏和视网膜变薄。总体而言，线粒体保护化合物，特别是基于SCQ的化合物，有潜力被开发成为治疗DR的有效且速效的候选药物。
