The role of EP2 in the long-lasting IOP reduction of JV-GL1 in ocular hypertensive mice
It is possible that the long-lasting IOP reduction in steroid-hypertensive mice is attributable to off-target effects of JV-GL1 apart from EP2 (e.g., by inhibiting the steroid response). To explore this possibility, we compared the effects of JV-GL1 between Ptger2-/- andPtger2+/+ littermates, all with steroid-induced ocular hypertension. A single bilateral periocular injection of dexamethasone-eluting nanoparticles increased IOP by 4.9 [3.8, 5.9] mmHg over 1 week (n=18; Supplemental Figure 3), with no significant differences observed between Ptger2-/- andPtger2+/+ littermates.
In hypertensive Ptger2 +/+ mice, a single unilateral dose of JV-GL1 (10 µl, 0.01%) reduced IOP after 3 hrs by -4.2 [-5.6, -2.9] mmHg relative to the vehicle-treated contralateral eye (P <0.0001; n=10 mice, Fig. 4). IOP reduction persisted for up to 4 days, when ΔIOP = ‑2.6 [‑3.3, -1.8] mmHg (P =0.02; n=10) but was undetectable by 6 days, when ΔIOP= -1.6 [‑2.8, ‑0.4] mmHg (P =0.7; n=10). In contrast, JV-GL1 had no effect on Ptger2-/- mice at 3 hours, when ΔIOP= 0.67 [‑0.3, 1.6] mmHg (P =1; n=8) nor any other time point. Thus, the long-lasting effect of JV-GL1 on IOP reduction does not appear to involve off-target effects, but appears to require EP2 receptor expression.