Abstract
Retinitis pigmentosa (RP) is a degenerative disease leading to photoreceptor cell loss. Mouse models of RP, such as the rd10 mouse (B6.CXBl-Pde6brd10/J), have enhanced our understanding of the disease, allowing for development of potential therapeutics. In 2011, our group first demonstrated that the synthetic progesterone analogue ‘Norgestrel’ is neuroprotective in two mouse models of retinal degeneration, including the rd10 mouse. We have since elucidated several mechanisms by which Norgestrel protects stressed photoreceptors, such as upregulating growth factors. This study consequently aimed to further characterize Norgestrel’s neuroprotective effects. Specifically, we sought to investigate the role that microglia might play; for microglial-derived inflammation has been shown to potentiate neurodegeneration. Dams of post-natal day (P) 10 rd10 pups were given a Norgestrel-supplemented diet (80mg/kg). Upon weaning, pups remained on Norgestrel. Tissue was harvested from P15-P50 rd10 mice on control or Norgestrel-supplemented diet. Norgestrel-diet administration provided significant retinal protection out to P40 in rd10 mice. Alterations in microglial activity coincided with significant protection, implicating microglial changes in Norgestrel-induced neuroprotection. Utilizing primary cultures of retinal microglia and 661W photoreceptor-like cells, we show that rd10 microglia drive neuronal cell death. We reveal a novel role of Norgestrel, acting directly on microglia to reduce pro-inflammatory activation and prevent neuronal cell death. Norgestrel effectively suppresses cytokine, chemokine and danger-associated molecular pattern molecule (DAMP) expression in the rd10 retina. Remarkably, Norgestrel upregulates fractalkine-CX3CR1 signaling 1 000-fold at the RNA level, in the rd10 mouse. Fractalkine-CX3CR1 signaling has been shown to protect neurons by regulating retinal microglial activation and migration. Ultimately, these results present Norgestrel as a promising treatment for RP, with dual actions as a neuroprotective and anti-inflammatory agent in the retina.
Highlights
Retinitis pigmentosa (RP) encompasses a set of hereditary diseases resulting in a progressive loss of rod and subsequently cone photoreceptors, leading to eventual blindness [1]
In this study we demonstrate the protective properties of the synthetic progestin ‘Norgestrel’, when administered via non-invasive diet supplementation
Through an upregulation of growth factors [12, 13], this study highlights a novel role for Norgestrel, in acting directly upon microglial cells to dampen damaging inflammatory processes
Summary
Retinitis pigmentosa (RP) encompasses a set of hereditary diseases resulting in a progressive loss of rod and subsequently cone photoreceptors, leading to eventual blindness [1]. A suitable model for studying cell death in RP, the course of photoreceptor cell loss and subsequent retinal degeneration in this mouse closely resembles disease progression in humans [5,6,7,8,9]. Published studies have since shown that Norgestrel, working through progesterone receptors [11], significantly increases production of basic fibroblast growth factor (bFGF) and leukemia inhibitory factor (LIF) in the retina [10, 12]. These growth factors likely act directly on photoreceptors to provide neuroprotection, through an upregulation of pro-survival and downregulation of apoptotic pathways [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
