Prokai-Tatrai Katalin, Zaman Khadiza, Kapic Ammar, Hogan Kelleigh, Sanchez-Rodriguez Gabriela, Silverio Anna E, Nguyen Vien, Prokai Laszlo, Feola Andrew J
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Center for Visual and Neurocognitive Rehabilitation, Joseph M. Cleland Atlanta VA Medical Center, Decatur, GA 30033, USA.
Int J Mol Sci. 2025 Feb 21;26(5):1846. doi: 10.3390/ijms26051846.
The association between 17β-estradiol (E2) deprivation, seen in menopause, and a risk for developing glaucoma has been shown. Thus, exogenous supplementation of E2 may protect against retinal ganglion cell (RGC) degradation and vision loss. Here, we investigated the utility of topical 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a prodrug of E2 that selectively produces the neuroprotective hormone in the retina, on visual function after optic nerve crush (ONC) and ovariectomy (OVX). We used female Brown Norway rats that underwent either Sham or OVX surgeries. After ONC, OVX animals received DHED or vehicle eye drops for 12 weeks. Visual function, via the optomotor reflex, and retinal thickness, via optical coherence tomography, were followed longitudinally. Afterward, we performed mass spectrometry-based label-free retina proteomics to survey retinal protein interaction networks in our selected animal model and to identify E2-responsive proteins after OVX on neurodegeneration. We found that ONC with OVX caused a significant decline in visual functions that were ameliorated by DHED treatments. Discovery-driven retina proteomics identified numerous proteins associated with neurodegenerative processes due to ONC that were remediated by DHED eye drops. Altogether, our three-pronged phenotypic preclinical evaluation of the topical DHED in the OVX + ONC model of glaucoma reveals the therapeutic potential of the prodrug to prevent visual deficits after glaucomatous retinal injury.
更年期出现的17β-雌二醇（E2）缺乏与患青光眼风险之间的关联已得到证实。因此，外源性补充E2可能预防视网膜神经节细胞（RGC）退化和视力丧失。在此，我们研究了局部应用10β,17β-二羟基雌-1,4-二烯-3-酮（DHED）（一种E2的前体药物，可在视网膜中选择性产生具有神经保护作用的激素）对视神经挤压（ONC）和卵巢切除术（OVX）后视觉功能的影响。我们使用接受了假手术或OVX手术的雌性挪威棕色大鼠。ONC后，OVX动物接受DHED或赋形剂眼药水滴眼12周。通过视动反射监测视觉功能，通过光学相干断层扫描监测视网膜厚度，并进行纵向跟踪。之后，我们进行了基于质谱的无标记视网膜蛋白质组学研究，以调查我们所选动物模型中的视网膜蛋白质相互作用网络，并确定OVX后E2反应性蛋白质对神经退行性变的影响。我们发现，ONC联合OVX导致视觉功能显著下降，而DHED治疗可改善这种情况。探索性视网膜蛋白质组学鉴定出许多与ONC导致的神经退行性过程相关的蛋白质，这些蛋白质可被DHED眼药水修复。总之，我们在青光眼OVX + ONC模型中对局部应用DHED进行的三方面表型临床前评估揭示了该前体药物预防青光眼性视网膜损伤后视力缺陷的治疗潜力。
