Cytoprotective Effects of a Novel Nrf2 Activator, RS9, in Rhodopsin Pro347Leu Rabbits

Abstract

ABSTRACTPurpose: Rhodopsin Pro347Leu transgenic rabbits were previously generated as models of retinitis pigmentosa (RP). While the mechanism underlying the retinal deterioration in these rabbits remains unresolved, it is likely that oxidative stress is one of the factors triggering cellular loss. We have recently succeeded in obtaining a novel activator (RS9) of nuclear factor erythroid 2-related factor (Nrf2, also known as NFE2L2), which regulates antioxidant transcriptional factors. The purpose of this study was to investigate whether RS9 delays progressive retinal degeneration in the transgenic rabbits.Methods: RS9 microspheres (3 mM, 50 µL) were injected into the vitreous of rhodopsin Pro347Leu transgenic rabbits at 6 weeks, after which outer nuclear layer (ONL) thickness was measured by optical coherence tomography. Rabbits were sacrificed at 15 weeks.Results: After intravitreal injection of RS9 microspheres, the concentration of RS9 in the vitreous was maintained at 1 nM for 2 weeks. At a concentration of 0.3 mM and 50 µL, RS9 significantly inhibited thinning of the ONL in transgenic rabbits compared to vehicle-injected transgenic rabbits. In RS9-injected transgenic rabbits, Nrf2-targeted genes had increased significantly, and levels of interleukin-6 mRNA decreased.Conclusions: Activation of Nrf2 signaling has potential as a novel approach for the prevention and treatment of RP, not only by driving intrinsic antioxidant enzymes, but also by inhibiting inflammatory responses. Although microspheres were employed in this study, small implants that release more compounds might be a realistic method for clinical trials.