Abstract
Purpose :
Neuronal endangerment that results from the disrupted interaction of photoreceptor (PR) cells and the retinal pigment epithelium (RPE) can be modeled by detachment of the retina from the RPE. This presents a direct model of the pathophysiology of retinal detachment (RD), and associated photoreceptor death and functional impairment. Induced RD also presents a test system for evaluation of the neuroprotective efficacy of interventions relevant to broader retinal indications. Advantages of the primate RD model are the consistency and rate with which the disease phenotype can be induced, the ability to quantify pathology, and an anatomy and pathophysiology highly homologous to humans. In this study, anatomic and histopathological features of RD induced by subretinal delivery of viscoelastics with and without neuroprotective test article were assessed over a five-day interval.
Methods :
Eyes of adult African green monkeys received subretinal injections of 0.5% hyaluronic acid (HA) formulated with Nec-1 and IDN-6556 (n=6 eyes), and without these cell death pathway inhibitors (n=6 eyes). Fundus and OCT images were collected at baseline, immediately post-RD (Day 0) and day 4 to assess the area of the detached retina and morphological change. On day 4 eyes were enucleated, post-fixed and processed to frozen sections for immunohistochemistry to assess apoptotic and GFAP positive cells.
Results :
The subretinal injection of HA induced a retinal detachment consisting of a circular bleb encompassing ~4 mm of the retinal region centered on the injection site within the superior arcade. Blebs were balanced in size and displacement with respect to treatment group. Raised blebs persisted for the 4-day duration of the study with slight volume loss. Immunohistochemistry revealed an increase in GFAP expression in the area of detached retina in all groups. CD11b+ staining revealed small infiltration of immune cells again restricted in the area of RD. TUNEL staining revealed dying PR cells in the detached area diminished in eyes treated with caspase and RIPK inhibitors.
Conclusions :
The study demonstrated that RDs consistent in size and location can be sustained over a period sufficient to induce neuronal injury. It was additionally demonstrated that the inhibition of the necrotic and apoptotic pathways by combined delivery of Nec-1 and IDN-6556, respectively, attenuated detected PR death.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.