TY - JOUR T1 - The role of EP<sub>2</sub> receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1 JF - British Journal of Ophthalmology JO - Br J Ophthalmol DO - 10.1136/bjophthalmol-2020-317762 SP - bjophthalmol-2020-317762 AU - Jacques A Bertrand AU - David F Woodward AU - Joseph M Sherwood AU - Jenny W Wang AU - Darryl R Overby Y1 - 2020/11/25 UR - http://bjo.bmj.com/content/early/2020/11/24/bjophthalmol-2020-317762.abstract N2 - Background A single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose. This highly protracted effect does not correlate with its ocular biodisposition or correlate with the once-daily dosing regimen for other prostanoid EP2 receptor agonists such as trapenepag or omidenepag. The underlying pharmacological mechanism for the multiday extended activity of JV-GL1 is highly intriguing. The present studies were intended to determine EP2 receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP2 receptors.Methods The protracted IOP reduction produced by JV-GL1 was investigated in C57BL/6J and EP2 receptor knock-out mice (B6.129-Ptger2tm1Brey/J; EP2KO). Both ocular normotensive and steroid-induced ocular hypertensive (SI-OHT) mice were studied. IOP was measured tonometrically under general anaesthesia. Aqueous humour outflow facility was measured ex vivo using iPerfusion in normotensive C57BL/6J mouse eyes perfused with 100 nM de-esterified JV-GL1 and in SI-OHT C57BL/6J mouse eyes that had received topical JV-GL1 (0.01%) 3 days prior.Results Both the initial 1-day and the protracted multiday effects of JV-GL1 in the SI-OHT model for glaucoma were abolished by deletion of the gene encoding the EP2 receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP2KO mice, but in littermate SI-OHT EP2WT control mice, JV-GL1 statistically significantly lowered IOP for 4–6 days.Conclusions Both the 1-day and the long-term effects of JV-GL1 on IOP are entirely EP2 receptor dependent. ER -