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Pharmaceutics. 2020 Jan 27;12(2). pii: E101. doi: 10.3390/pharmaceutics12020101.

17β-Estradiol Delivered in Eye Drops: Evidence of Impact on Protein Networks and Associated Biological Processes in the Rat Retina through Quantitative Proteomics.

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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.


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.


biological networks; crystallin; estradiol; eye drops; female rats; label-free quantitation; pathway analysis; proteomics; retina; target engagement

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Conflict of interest statement

L.P. and K.P.-T. are inventors in the patents covering the use of a bioprecursor prodrugs for estrogens as ophthalmic agents and are co-founders of AgyPharma LLC with equity in the company that licensed the patents. K.Z. and V.N. declare no conflict of interest.

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