The role of EP 2 receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.
Bertrand Jacques A, Woodward David F, Sherwood Joseph M, Wang Jenny W, Overby Darryl R
AI Summary
JV-GL1's ultra-long IOP reduction in glaucoma models is entirely dependent on EP2 receptors, suggesting a novel, sustained therapeutic approach for lowering eye pressure.
Abstract
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 EP 2 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 EP 2 receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP 2 receptors.
Methods
The protracted IOP reduction produced by JV-GL1 was investigated in C57BL/6J and EP 2 receptor knock-out mice (B6.129- Ptger2 tm1Brey /J; EP 2 KO). 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 EP 2 receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP 2 KO mice, but in littermate SI-OHT EP 2 WT 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 EP 2 receptor dependent.
MeSH Terms
Shields Classification
Key Concepts5
The initial 1-day and the protracted multiday effects of JV-GL1 in the steroid-induced ocular hypertensive (SI-OHT) mouse model for glaucoma were abolished by deletion of the gene encoding the EP2 receptor.
JV-GL1 did not lower intraocular pressure (IOP) in steroid-induced ocular hypertensive (SI-OHT) EP2 receptor knock-out (KO) mice.
JV-GL1 statistically significantly lowered intraocular pressure (IOP) for 4-6 days in littermate steroid-induced ocular hypertensive (SI-OHT) EP2 wild-type (WT) control mice.
Both the 1-day and the long-term effects of JV-GL1 on intraocular pressure (IOP) are entirely EP2 receptor dependent.
A single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose.
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