17β-Estradiol Eye Drops Protect the Retinal Ganglion Cell Layer and Preserve Visual Function in an in Vivo Model of Glaucoma

Abstract

Neuroprotection in glaucoma as a curative strategy complementary to current therapies to lower intraocular pressure (IOP) is highly desirable. This study was designed to investigate neuroprotection by 17β-estradiol (E2) to prevent retinal ganglion cell (RGC) death in a glaucoma model of surgically elevated IOP in rats. We found that daily treatment with E2 containing eye drops resulted in significant E2 concentration in the retina with concomitant profound neuroprotective therapeutic benefits, even in the presence of continually elevated IOP. The number of apoptotic cells in the RGC layer was significantly decreased in the E2-treated group, when compared to the vehicle-treated controls. Deterioration in visual acuity in these animals was also markedly prevented. Using mass spectrometry-based proteomics, beneficial changes in the expression of several proteins implicated in the maintenance of retinal health were also found in the retina of E2-treated animals. On the other hand, systemic side-effects could not be avoided with the eye drops, as confirmed by the measured high circulating estrogen levels and through the assessment of the uterus representing a typical hormone-sensitive peripheral organ. Collectively, the demonstrated significant neuroprotective effect of topical E2 in the selected animal model of glaucoma provides a clear rationale for further studies aiming at targeting E2 into the eye while avoiding systemic E2 exposure to diminish undesirable off target side-effects.

The estrogenic retina: The potential contribution to healthy aging and age-related neurodegenerative diseases of the retina

“…αA-crystallin is a chaperone-like protein involved in remodeling cytoskeleton and preventing protein aggregation, inflammation and apoptosis, and with supposed implications in aging, glaucoma, diabetes, Alzheimer and other neurodegenerative diseases (for review, see [136]). A similar αA-crystallin increase along with retinal protection has been recently detected following treatment with oestradiol drops [137].…”

Gender Difference in the Pathophysiology and Treatment of Glaucoma

“…9 Next, retinal ganglion cells (the neurons susceptible to glaucomatous damage) express estrogen receptors, and signaling through estrogen receptors may offer cellular protection (also referred to as neuroprotection) for retinal ganglion cells. 88,89 Indeed, the neuroprotective effects of estrogen in the central nervous system are well documented, [90][91][92][93][94][95][96][97][98] and estrogen may offer neuroprotection of axons within the optic nerve as well. Estrogen may also have a protective effect by increasing extracellular matrix production.…”

“…109 Thus, although it appears to be mild, though statistically significant benefit from the use of HT with estrogen in association with OAG diagnosis, based on the current literature and the USPSTF recommendation, HT should not be used for the purpose of glaucoma prevention or treatment. Interestingly, topical 17-beta-estradiol eye drops have been shown to enhance retinal ganglion cell survival in an animal model of glaucoma, 89 and Another form of exogenous HT in pre-menopausal women is the use of OCs. The Nurses' Health Study followed 79,440 women aged 40 years or older from 1980 to 2006, who were free of OAG at baseline.…”

Excitotoxicity and Glaucoma

“…Therefore, agents that effectively enhance glutamate transporter function may serve as potential therapeutics against the pressure-induced injury. Enhancement of glutamate transport is developing into a new strategy for reducing excitotoxicity also in brain injury and neurodegenerative disease [69][70][71]. Lee et al (2009) [72] reported that tamoxifen, estrogen modulator, possessed neuroprotective properties against excitotoxicity by the up-regulation of GLAST at protein and mRNA levels in the mannganeseinduced excitotoxicity.…”