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).