Prokai Laszlo, Zaman Khadiza, Nguyen Vien, Prokai-Tatrai Katalin
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Pharmaceutics. 2020 Jan 27;12(2):101. doi: 10.3390/pharmaceutics12020101.
To facilitate the development of broad-spectrum retina neuroprotectants that can be delivered through topical dosage forms, this proteomics study focused on analyzing target engagements through the identification of functional protein networks impacted after delivery of 17β-estradiol in eye drops. Specifically, the retinae of ovariectomized Brown Norway rats treated with daily eye drops of 17β-estradiol for three weeks were compared to those of vehicle-treated ovariectomized control animals. We searched the acquired raw data against a composite protein sequence database by using Mascot, as well as employed label-free quantification to detect changes in protein abundances. Our investigation using rigorous validation criteria revealed 331 estrogen-regulated proteins in the rat retina (158 were up-regulated, while 173 were down-regulated by 17β-estradiol delivered in eye drops). Comprehensive pathway analyses indicate that these proteins are relevant overall to nervous system development and function, tissue development, organ development, as well as visual system development and function. We also present 18 protein networks with associated canonical pathways showing the effects of treatments for the detailed analyses of target engagements regarding potential application of estrogens as topically delivered broad-spectrum retina neuroprotectants. Profound impact on crystallins is discussed as one of the plausible neuroprotective mechanisms.
为促进可通过局部剂型给药的广谱视网膜神经保护剂的开发，这项蛋白质组学研究聚焦于通过识别滴眼剂中17β-雌二醇给药后受影响的功能性蛋白质网络来分析靶点参与情况。具体而言，将连续三周每日用17β-雌二醇滴眼剂治疗的去卵巢棕色挪威大鼠的视网膜与用赋形剂处理的去卵巢对照动物的视网膜进行比较。我们使用Mascot在复合蛋白质序列数据库中搜索所获取的原始数据，并采用无标记定量法来检测蛋白质丰度的变化。我们使用严格的验证标准进行的研究揭示了大鼠视网膜中有331种雌激素调节蛋白（滴眼剂中17β-雌二醇使158种蛋白上调，173种蛋白下调）。全面的通路分析表明，这些蛋白质总体上与神经系统发育和功能、组织发育、器官发育以及视觉系统发育和功能相关。我们还展示了18个具有相关典型通路的蛋白质网络，这些网络显示了治疗效果，以便对雌激素作为局部给药的广谱视网膜神经保护剂的潜在应用进行靶点参与情况的详细分析。对晶状体蛋白的深远影响被作为一种可能的神经保护机制进行了讨论。
