Sex differences in in vitro and in vivo glaucoma models may predict gender specific dose adjustment needs

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PROJECT SUMMARY One of the most definite epidemiological characteristics of primary open angle glaucoma (POAG) is that, its incidence shows a strong sex-related difference. Nitric oxide (NO) is directly implicated in the regulation of intraocular pressure (IOP) in glaucoma. Our laboratory is currently working on design, synthesis and testing of a novel hybrid class of NO donors to lower IOP with neuroprotective activity in rodent models. Several epidemiological studies have suggested that estrogen levels correlate positively to increased retinal blood circulation, increased NO synthesis and negatively with intra ocular pressure (IOP) levels. Estrogen increases the activity of endothelial-based nitric oxide synthase (NOS) and therefore regulates smooth muscle tone and vascular resistance. Since estrogen receptors are located in the trabecular meshwork, ciliary body and the outflow system of the eye, it might potentially influence IOP by regulating both aqueous humor production and outflow. Consequently, there may be gender-dependent differential response to anti-glaucoma drugs especially to that simultaneously deliver NO along with antioxidant activity which interfere with estrogen signaling in men and women. The goal of this project is to determine the gender specific effects of the NO donating- antioxidant hybrid compounds on the trabecular meshwork (TM) cell’s anti-oxidant enzyme status, extracellular matrix composition, estrogen regulating enzyme levels and on the overall IOP lowering activity. We have synthesized a novel multifunctional hybrid anti-oxidant and NO donating compound SA-2 as well as several other novel highly antioxidant derivatives of SA-2 compound. Our published results ensued from this project demonstrated that a single eye drop of a nano encapsulated suspension of SA-2 lowered IOP by 50% in mouse as well as in rat glaucoma model (in both males and females). Additionally, compound SA-2 is neuroprotective ex vivo in hypoxia treated retinal explants and in the in vivo IOP-independent optic nerve crush (ONC) model performed in female mice. In our preliminary result using human trabecular meshwork (hTM) cells, we found that there is a gender dependent difference in the cytoprotective activity of SA-2 at 1mM dose. We further found that, the female mice respond differently than male mice when subjected to ONC injury. Specifically, for this NIH supplement application, we propose to use primary human hTM cell derived both from female and male donors (specific aim 1) as well as in glaucomatous TM tissues from three animal groups: females, males and ovariectomized (OVX) females, in which OVX procedure models a postmenopausal state (specific aim 2). We hypothesize that, compound SA-2 and its novel analog SA-10 will have differential cellular and molecular activities depending on the gender and estrogen-related signaling. Successful completion of the proposed studies will have an implication for developing novel therapeutics for glaucoma with emphasis to a gender differences to help design more personalized therapies along with gender specific dose adjustment.