Introduction
Primary open-angle glaucoma is the second leading cause of blindness (Resnikoff et al. , 2004). First-line glaucoma therapy typically consists of eye drops that lower intraocular pressure (IOP) and containing prostaglandin analogues such as bimatoprost, latanoprost, and travoprost (Sambhara and Aref, 2014). These drugs primarily target the uveoscleral tissues (Schachtschabel, Lindsey and Weinreb, 2000; Winkler and Fautsch, 2014), lowering resistance to aqueous humour outflow, reducing IOP, and thereby protecting retinal ganglion cells from pressure induced damage. Once daily dosing is required to effectively manage IOP, however 25% of patients are non-responders (Scherer, 2002; Sakurai et al. , 2014), and poor patient compliance is commonplace (Okeke et al. , 2009; Boland et al. , 2014). Poor compliance correlates with more severe visual field loss (Sleath et al. , 2012). It follows that a relaxed dosing regimen, for example once or twice weekly with a long acting drug, may improve compliance and treatment outcomes accordingly.
JV-GL1 (PGN 9856-isopropyl ester), was recently reported as a highly selective and potent EP2 receptor agonist (Colemanet al. , 2018), which profoundly lowers IOP in Cynomolgus monkeys for an unprecedented duration of 5-10 days after a single dose (Woodward, et al. , 2019a). The well-researched EP2 agonist, butaprost (Nilsson et al. , 2006), and the more contemporary EP2 agonists taprenepag (Prasanna et al. , 2011) and omnidenepag isopropyl (Fuwa et al. , 2018) have comparatively short 24 hour durations of action.
Understanding the mechanism behind the uniquely long-acting ocular hypotensive effect of JV-GL1 is of interest in the development of superior ocular hypotensive agents. Given the lack of correlation between the ultra-long duration of action of JV-GL1 and its relatively short bioavailability in the eye (Woodward et al., 2019a), an EP2 receptor mediated mechanism seemed unlikely. In the present investigations, we examined the IOP-lowering effect of JV-GL1 in ocular normotensive and hypertensive mice. Ocular hypertension was induced in mice using a recently developed method of locally injected dexamethasone eluting nanoparticles (Agrahari, 2017; Wang et al. , 2018). The role of the EP2 receptor in mediating the IOP effects of JV-GL1 was then investigated using EP2receptor deleted mice (Kennedy et al. , 1999).