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Effect of INS37217, a P2Y₂ Receptor Agonist, on Experimental Retinal Detachment and Electroretinogram in Adult Rabbits

¹ From the Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina; ² Inspire Pharmaceuticals, Inc., Durham, North Carolina; and the ³ Department of Biomedical Engineering, Duke University, Durham, North Carolina.

PURPOSE. To evaluate the effects of subretinal and intravitreal delivery of INS37217, a P2Y₂ receptor agonist, on subretinal fluid reabsorption in experimentally induced retinal detachments in rabbits, and to characterize the effects of INS37217 on electroretinograms (ERG) in rabbits.

METHODS. A single retinal detachment was produced in New Zealand White rabbits by injecting approximately 50 µL of modified phosphate-buffered saline (MPBS) solution into the subretinal space (SRS). In all experiments, one eye served as the INS37217-treated eye and the contralateral eye served as the vehicle control. In the first series of experiments, each rabbit received a SRS injection of MPBS solution, with or without INS37217 (1 mM). In the second series of experiments, each eye received an SRS injection of MPBS solution, followed by an intravitreal injection of MPBS solution, with or without INS37217 (12, 1.4, and 0.15 mM). A masked observer determined the size of blebs by indirect ophthalmoscopy at 30-minute intervals for up to 3 hours after SRS injections. Optical coherence tomography (OCT) was conducted to provide cross-sectional images of the blebs. Cellular expression of P2Y₂ receptor mRNA was localized by nonradioisotopic in situ hybridization in fresh rabbit retina–RPE tissue sections. Bilateral, full-field scotopic and photopic ERGs were made at 1, 7, and 14 days after a single intravitreal injection of 24 mM INS37217.

RESULTS. SRS administration of 1 mM INS37217 significantly enhanced subretinal fluid reabsorption when compared with vehicle controls (P < 0.05; repeated measures ANOVA). Intravitreal administration of INS37217 at 12 and 1.4 mM, but not at 0.15 mM, also significantly enhanced subretinal fluid reabsorption (P < 0.05). P2Y₂ receptor mRNA was observed throughout the RPE and in discrete layers of the retina. INS37217 had no adverse effects on scotopic and photopic ERG amplitude and latency parameters at any of the postadministration time points evaluated.

CONCLUSIONS. These results demonstrate that INS37217 enhances subretinal fluid reabsorption in experimental retinal detachment in rabbits and support the development of INS37217 for stimulating subretinal fluid reabsorption in conditions that result in retinal detachment or retinal edema.

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