Rapamycin Inhibits Retinal and Choroidal Neovascularization in Mice

Abstract

Abstract: : Purpose:Ocular neovascularization is a major cause of blindness and treatments are not always successful. Many antiangiogenic agents have been developed and some have shown promise in inhibiting ocular neovascularization; however, their efficacy has not been determined clinically. Rapamycin (RAPA) is clinically used as an immunosuppressant. In this study, we tested the effects of RAPA on models of ischemia- induced retinal neovascularization and laser-induced choroidal neovascularization (CNV). Methods:In order to induce retinal neovascularization, adult C57BL/6 mice (P7) were exposed to 75% oxygen for 5 days and then returned to room air. Mice subsequently received intraperitoneal (IP) injections of RAPA (2mg/kg/day or 4mg/kg/day) from P12 to P19. On P19, eyes were enucleated and processed for paraffin sectioning. Sections (5 mm) were obtained and retinal neovascularization was quantified. In order to induce CNV, C57BL/6 mice underwent laser photocoagulation to rupture Bruch’s membrane. Following surgery, animals received daily IP injections of RAPA (2mg/kg/day or 4mg/kg/day) or phosphate-buffered saline (PBS) for 2 weeks. Animals were perfused with fluorescein isothiocyanante-dextran, eyes were enucleated and then subsequently fixed in 4% paraformaldehyde. Flat mounts were prepared and CNV was quantified. Results:Retinal neovascularization was significantly reduced in the animals exposed to hyperoxia and subsequently treated with RAPA when compared to control animals (p<0.001). In addition, CNV was reduced in animals undergoing laser photocoagulation following RAPA treatment when compared to controls (2mg/kg/day, p<0.05; 4mg/kg/day, p<0.001). The 4mg/kg/day RAPA treatment decreased the size of CNV by 40%. Conclusions:The immunosuppressive drug RAPA can inhibit ischemic-induced retinal neovascularization and laser-induced CNV in mice. Additional studies must confirm the utility and safety of RAPA treatment before considering application to human neovascular disease.

Keywords: retinal neovascularization • choroid: neovascularization • drug toxicity/drug effects