Norgestrel, a
progesterone analogue, has demonstrated
neuroprotective effects in a mouse model of
retinitis pigmentosa. Neuroprotection is achieved in part through Norgestrels anti-inflammatory properties, alleviating detrimental microglial activity.
Gliosis is a feature of many
neurodegenerative diseases of the retina, including
retinitis pigmentosa. Müller glia, a type of macroglia found in the retina, are major contributors of
gliosis, characterized by the upregulation of
glial fibrillary acidic protein (GFAP). Microglia-Müller glia crosstalk has been implicated in the initiation of
gliosis. In the rd10 retina, increased microglial activity and gliotic events are observed prior to the onset of photoreceptor loss. We hypothesized that Norgestrels dampening effects on harmful microglial activity would consequently impact on
gliosis. In the current study, we explore the role of microglia-Müller glia crosstalk in degeneration and
Norgestrel-mediated neuroprotection in the rd10 retina. Norgestrels
neuroprotective effects in the rd10 retina coincide with significant decreases in both microglial activity and Müller cell
gliosis. Using a Müller glial cell line, rMC-1, and isolated microglia, we show that rd10 microglia stimulate GFAP production in rMC-1 cells.
Norgestrel attenuates
gliosis through direct actions on both microglia and Müller glia.
Norgestrel reduces the release of harmful stimuli from microglia, such as
interferon-γ, which might otherwise signal to Müller glia and stimulate
gliosis. We propose that
Norgestrel also targets Müller cell
gliosis directly, by limiting the availability of pSTAT3, a known
transcription factor for GFAP. These findings highlight an important aspect to Norgestrels
neuroprotective effects in the diseased retina, in combating Müller cell
gliosis.