'
Norgestrel', a synthetic form of the female
hormone progesterone has been identified as potential
drug candidate for the treatment of the degenerative
eye disease retinitis pigmentosa. However, to date, no work has looked at the compound's specific cellular target. Therefore, this study aimed to identify the receptor target of
Norgestrel and begin to examine its potential mechanism of action in the retina. In this work, we identify and characterize the expression of
progesterone receptors present in the C57 wild type and rd10 mouse model of
retinitis pigmentosa. Classical
progesterone receptors A and B (PR A/B),
progesterone receptor membrane components 1 and 2 (PGRMC1, PGRMC2) and membrane
progesterone receptors α, β and γ were found to be expressed. All receptors excluding PR A/B were also found in the 661W photoreceptor cell line. PGRMC1 is a key regulator of apoptosis and its expression is up-regulated in the degenerating rd10 mouse retina. Activated by
Norgestrel through nuclear trafficking,
siRNA knock down of PGRMC1 abrogated the protective properties of
Norgestrel on damaged photoreceptors. Furthermore, specific inhibition of PGRMC1 by
AG205 blocked
Norgestrel-induced protection in stressed
retinal explants. Therefore, we conclude that PGRMC1 is crucial to the
neuroprotective effects of
Norgestrel on stressed photoreceptors. The
synthetic progestin '
Norgestrel' has been identified as a potential therapeutic for the treatment of
Retinitis Pigmentosa, a degenerative
eye disease. However, the mechanism behind this neuroprotection is currently unknown. In this work, we identify '
Progesterone Receptor Membrane Component 1' as the major
progesterone receptor eliciting the protective effects of
Norgestrel, both in vitro and ex vivo. This furthers our understanding of
Norgestrel's molecular mechanism, which we hope will help bring
Norgestrel one step closer to the clinic.