title: Cytoprotective Effects of a Novel Nrf2 Activator, RS9, in Rhodopsin Pro347Leu Rabbits.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: a Daiichi Sankyo Co., Ltd ., Tokyo , Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakagami
authors.affiliation: a Daiichi Sankyo Co., Ltd ., Tokyo , Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Hatano
authors.affiliation: a Daiichi Sankyo Co., Ltd ., Tokyo , Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Inoue
authors.affiliation: a Daiichi Sankyo Co., Ltd ., Tokyo , Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: b Department of Ophthalmology , Mie University Graduate School of Medicine , Tsu , Japan.
authors.forename: Mineo
authors.initials: M
authors.lastname: Kondo
authors.affiliation: c Department of Ophthalmology Protective Care for Sensory Disorders , Nagoya University Graduate School of Medicine , Nagoya , Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Terasaki
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004596:Electroretinography; D058449:Intravitreal Injections; D051267:NF-E2-Related Factor 2 / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D012174:Retinitis Pigmentosa / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics* / Q000378:metabolism; D041623:Tomography, Optical Coherence; D014315:Triterpenes / Q000008:administration & dosage*
chemical_list: D051267:NF-E2-Related Factor 2; C000602880:RS9 triterpenoid; D014315:Triterpenes; D012243:Rhodopsin
keywords: Nrf2; RS9; optical coherence tomography; retinitis pigmentosa; rhodopsin