Abstract
Oxidative stress induced death and dysregulation of trabecular meshwork (TM) cells contribute to the increased intraocular pressure (IOP) in primary open angle (POAG) glaucoma patients. POAG is one of the major causes of irreversible vision loss worldwide. Nitric oxide (NO), a small gas molecule, has demonstrated IOP lowering activity in glaucoma by increasing aqueous humor outflow and relaxing TM. Glaucomatous pathology is associated with decreased antioxidant enzyme levels in ocular tissues causing increased reactive oxygen species (ROS) production that reduce the bioavailability of NO. Here, we designed, synthesized, and conducted in vitro studies of novel second-generation sulfur containing hybrid NO donor-antioxidants SA-9 and its active metabolite SA-10 to scavenge broad-spectrum ROS as well as provide efficient protection from t-butyl hydrogen peroxide (TBHP) induced oxidative stress while maintaining NO bioavailability in TM cells. To allow a better drug delivery, a slow release nanosuspension SA-9 nanoparticles (SA-9 NPs) was prepared, characterized, and tested in dexamethasone induced ocular hypertensive (OHT) mice model for IOP lowering activity. A single topical eye drop of SA-9 NPs significantly lowered IOP (61%) at 3 h post-dose, with the effect lasting up to 72 h. This class of molecule has high potential to be useful for treatment of glaucoma.
Highlights
Primary open angle glaucoma (POAG) is among the leading causes of irreversible blindness globally
The hybrid molecule SA-2 quickly hydrolyzes in physiological, aqueous environments, and an effective sustained release of SA-2 could be achieved by packaging it in a Polylactic-co-glycolic acid (PLGA) nanoparticle carrier [16]
Using a published protocol developed by Patel et al [18], we evaluated SA-9 NPs eye drop in a DexAc induced ocular hypertensive (OHT) mouse eye model for its ability to lower intraocular pressure (IOP)
Summary
Primary open angle glaucoma (POAG) is among the leading causes of irreversible blindness globally. POAG is associated with compromised trabecular meshwork (TM), decreased aqueous humor outflow, increased intraocular pressure (IOP) [1], and degeneration of optic nerve head, altogether resulting in progressive vision loss. Despite damage to the TM, POAG is considered a multifactorial disease in which aging, inflammation, neurotrophic factors, genetics, and oxidative stress may play key roles in the pathophysiology [2]. Elevated IOP is an important risk factor for the development and progression of POAG. The IOP elevation in glaucoma is caused by the increased resistance to aqueous humor outflow, leading to ischemia and decreased oxygen supply to the retina, which progressively results in retinopathy. Treatment options have essentially focused on reducing IOP and increasing aqueous humor outflow or decreasing aqueous humor formation.
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