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P. Koulen, H. Xin, V. Nguyen, K. Prokai-Tatrai, L. Prokai; Unprecedented Protection of the Retina in a Rat Model for Glaucoma by Topical Administration of a Novel Prodrug for 17β-Estradiol. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4327.
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While a majority of pharmacological approaches presently target intraocular pressure (IOP) lowering therapies, non-IOP lowering glaucoma therapies are needed to complement them. Estrogens are powerful neuroprotectants and have been considered potential drugs to protect the retina against neurodegenerative effects caused by glaucoma. The "feminizing" effect of estrogens after systemic administration and their poor ocular bioavailability, however, hinder their development as practical and topically applied ocular drugs. We report our discovery that a novel prodrug of 17β-estradiol (E2), 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), avoids these setbacks by selectively converting in vivo to E2 inside the eye.
Transcorneal permeability and prodrug conversion rates in ocular tissues were measured in vitro. Histology and TUNEL assays were used to measure cell death in the retinal ganglion cell layer (GCL) of a model of glaucoma where IOP had been surgically elevated in ovariectomized rats. Visual acuity was measured and correlated with the histological parameters. Treatments were administered topically as eyedrops and animals were sacrificed 19-30 days after IOP elevation.
Transcorneal permeability of DHED was 10-times higher than that of E2. The DHED to E2 conversion rate in rat retina was the highest among all ocular and non-ocular tissues tested. A significant protection of the GCL was observed (reduction in apoptic cell numbers) in the DHED group, yet IOP remained unchanged when compared to the vehicle treated group. Visual function measured as contrast sensitivity at a given spatial frequency was significantly preserved with E2 and DHED treatment. We also measured that peripheral exposure to E2 was avoided after DHED administration.
In vivo ocular neuroprotective effects achieved by the topical treatment with DHED far exceed those of existing or experimental ophthalmic drugs.
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