PDF(Pubmed)
Abstract：
We report a three-pronged phenotypic evaluation of the bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) that selectively produces 17β-estradiol (E2) in the retina after topical administration and halts glaucomatous neurodegeneration in a male rat model of the disease. Ocular hypertension (OHT) was induced by hyperosmotic saline injection into an episcleral vein of the eye. Animals received daily DHED eye drops for 12 weeks. Deterioration of visual acuity and contrast sensitivity by OHT in these animals were markedly prevented by the DHED-derived E2 with concomitant preservation of retinal ganglion cells and their axons. In addition, we utilized targeted retina proteomics and a previously established panel of proteins as preclinical biomarkers in the context of OHT-induced neurodegeneration as a characteristic process of the disease. The prodrug treatment provided retina-targeted remediation against the glaucomatous dysregulations of these surrogate endpoints without increasing circulating E2 levels. Collectively, the demonstrated significant neuroprotective effect by the DHED-derived E2 in the selected animal model of glaucoma supports the translational potential of our presented ocular neuroprotective approach owing to its inherent therapeutic safety and efficacy.
摘要：
我们报告了生物前体前药10β的三管齐下的表型评估，17β-二羟基雌二醇-1,4-dien-3-酮（DHED），在局部给药后在视网膜中选择性产生17β-雌二醇（E2），并在该疾病的雄性大鼠模型中停止青光眼神经变性。通过将高渗盐水注射到眼睛的巩膜静脉中引起眼部高血压（OHT）。动物每天接受DHED滴眼剂,持续12周。DHED衍生的E2可显着防止这些动物中OHT引起的视敏度和对比敏感度下降，同时保留了视网膜神经节细胞及其轴突。此外,我们利用靶向视网膜蛋白质组学和先前建立的一组蛋白质作为OHT诱导的神经变性的临床前生物标志物作为疾病的特征性过程.前药治疗提供了针对这些替代终点的青光眼失调的视网膜靶向治疗,而不增加循环E2水平。总的来说，在选定的青光眼动物模型中,DHED衍生的E2具有显著的神经保护作用,由于其固有的治疗安全性和有效性,支持我们提出的眼部神经保护方法的翻译潜力.
