A Novel Neuroprotective Approach for Glaucoma

ABSTRACT The broad goal of our continued research is to decipher the effect of estrogen deprivation, with or without elevated intraocular pressure (IOP), on the vulnerability of the retina to neurodegeneration and to find a preventative and/or curative pharmacological intervention to preserve the quality of vison under these conditions. In the current grant period, we have shown that our prodrug approach (DHED) has produced the powerful neuroprotectant, 17β-estradiol (E2), exclusively in the retina upon topical administration without exposing the rest of the body to the unwanted side effects of the hormone. This distinguishing feature of DHED has been demonstrated in both male and female animals. In an animal model of human glaucoma, we have found that E2 produced locally from DHED protects the retinal ganglion cells (RGCs) from apoptosis, as well as prevents visual impairment and functional deficits associated with the disease. Using proteomics, we have also found that DHED eye drops successfully engaged E2-responsive therapeutic targets in the rat retinal proteome. Through these studies, we have recognized that young, gonadectomized male and female animals with normotensive IOP exhibit a proteomic landscape that is very similar to that of aged animals when compared to young intact animals. Elevated IOP further disrupted vital protein expressions associated with signaling networks involving neuroprotective targets and regulations of metabolic activities essential for retina health. However, DHED eye drops completely alleviated the detrimental consequences of estrogen deprivation and elevated IOP, suggesting that an “estrogenic” retina is needed for proper visual function. This application for renewal addresses critical questions that stem from these collective findings. Specifically, is an E2-deprived retina, regardless of age or elevated IOP, vulnerable to neurodegeneration, and can topical DHED be used as a preventative and therapeutic agent to preserve the quality of vison under hypoestrogenic and/or elevated IOP condition? Specific Aim 1 is designed to determine parameters of RGC neuroprotection and for the attenuation of visual impairment afforded by DHED eye drops in E2-deprived animals compared to normotensive and hypertensive ocular conditions. Proteomics- and phosphoproteomics-based studies in Specific Aim 2 will investigate the mechanistic benefits of DHED eye drops in E2-deprived animals that exhibit normal versus elevated IOP. Specific Aim 3 will utilize retina metabolomics to address metabolic dysregulations under hypoestrogenic conditions and elevated IOP, compared to the amelioration of these alterations by topical DHED. Through the integration of functional vision analyses with a multi-omics approach, we seek to advance our understanding of E2 deprivation- and IOP-triggered ocular neurodegeneration, as well as its prevention or treatment by topical DHED, in a comprehensive fashion.