Pro‐survival redox signalling in progesterone‐mediated retinal neuroprotection

Retinitis pigmentosa (RP) is a group of hereditary retinal diseases, characterised by photoreceptor cell loss. Despite a substantial understanding of the mechanisms leading to cell death, an effective therapeutic strategy is sought. Our laboratory has previously demonstrated the neuroprotective properties of Norgestrel, a progesterone analogue, in the degenerating retina, mediated in part by the neurotrophic factor basic fibroblast growth factor (bFGF). In other retinal studies, we have also presented a pro‐survival role for reactive oxygen species (ROS), downstream of bFGF. Thus, we hypothesized that Norgestrel utilises bFGF‐driven ROS production to promote photoreceptor survival. Using the 661W photoreceptor‐like cell line, we now show that Norgestrel, working through progesterone receptor membrane complex 1 (PGRMC1); generates an early burst of pro‐survival bFGF‐induced ROS. Using the rd10 mouse model of RP, we confirm that Norgestrel induces a similar early pro‐survival increase in retinal ROS. Norgestrel‐driven protection in the rd10 retina was attenuated in the presence of antioxidants. This study therefore presents an essential role for ROS signalling in Norgestrel‐mediated neuroprotection in vitro and demonstrates that Norgestrel employs a similar pro‐survival mechanism in the degenerating retina. The progesterone analogue Norgestrel works through the progesterone receptor membrane complex 1 (PGRMC1), stimulating the production of the neurotrophic factor bFGF in serum‐starved 661W cells. Norgestrel utilises bFGF‐driven ROS production to promote photoreceptor survival at early stages.