title: The synthetic progestin norgestrel modulates Nrf2 signaling and acts as an antioxidant in a model of retinal degeneration.
abstract: Retinitis pigmentosa (RP) is one of the most common retinal degenerative conditions affecting people worldwide, and is currently incurable. It is characterized by the progressive loss of photoreceptors, in which the death of rod cells leads to the secondary death of cone cells; the cause of eventual blindness. As rod cells die, retinal-oxygen metabolism becomes perturbed, leading to increased levels of reactive oxygen species (ROS) and thus oxidative stress; a key factor in the secondary death of cones. In this study, norgestrel, an FDA-approved synthetic analog of progesterone, was found to be a powerful neuroprotective antioxidant, preventing light-induced ROS in photoreceptor cells, and subsequent cell death. Norgestrel also prevented light-induced photoreceptor morphological changes that were associated with ROS production, and that are characteristic of RP. Further investigation showed that norgestrel acts via post-translational modulation of the major antioxidant transcription factor Nrf2; bringing about its phosphorylation, subsequent nuclear translocation, and increased levels of its effector protein superoxide dismutase 2 (SOD2). In summary, these results demonstrate significant protection of photoreceptor cells from oxidative stress, and underscore the potential of norgestrel as a therapeutic option for RP.
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Ashleigh M
authors.initials: AM
authors.lastname: Byrne
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ruiz-Lopez
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Roche
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Moloney
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
authors.forename: Alice C
authors.initials: AC
authors.lastname: Wyse-Jackson
authors.affiliation: Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland. Electronic address: t.cotter@ucc.ie.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Cotter
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009644:Norgestrel / Q000008:administration & dosage* / Q000494:pharmacology; D010766:Phosphorylation; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D009644:Norgestrel; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C495636:Nfe2l2 protein, mouse
keywords: Norgestrel; Nrf2; Photoreceptors; ROS; Retinitis pigmentosa