Fig. 8

A Non-classical progestin signaling. PGRMC1 has been found to be highly expressed in the 661 W photoreceptor cell line, RPE, and MG [52, 53]. Norgestrel has been shown to exhibit antioxidant properties, preventing photoreceptor damage in a model for RP via increasing the expression of Nrf2, which in response to oxidative stress, binds to DNA anti-oxidant response elements and initiates the transcription of cytoprotective genes [54,55,56]. Huang et al. [57] suggested that it is the phosphorylation of Nrf2 by protein kinase C that induces Nrf2’s nuclear translocation and anti-oxidant effects. B Norgestrel exhibits neuroprotective properties in stressed photoreceptor-like cells and retinal explants via upregulating basic fibroblast growth factor (bFGF) activity via a protein kinase A pathway-dependent mechanism. bFGF phosphorylates and inactivates glycogen synthase kinase 3-beta (GSK3B), preventing the dysregulation of the Nrf2 defense system via preventing the phosphorylating FYN which induces the nuclear export and degradation of Nrf2 [56, 58, 59]. C Norgestrel upregulates fractalkine-CX3CR1 signaling in 661 W cells and C57 explants and fractalkine signaling which mediates norgestrel cytoprotection via reduction of inflammatory cytokine production in rd10 microglia [60]. Pie charts adjacent to proteins represent the protein’s relative abundance in the periphery (blue), macula (orange), and fovea (gray) based on the mass spectrometry data provided by the Skeie and Mahajan [5] study