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Violeta Gomez-Vicente, Laura Fernandez-Sanchez, Gillian Groeger, Francesca Doonan, Tom Cotter, Nicolas Cuenca; Neuroprotective effects of norgestrel in retinitis pigmentosa: preservation of retinal cytoarchitecture and synaptic connectivity. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4200.
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© ARVO (1962-2015); The Authors (2016-present)
Norgestrel is a synthetic progestin commonly used in hormonal contraception, which has recently demonstrated strong neuroprotective activity in two in vivo models of retinal degeneration, the light damage model and the rd10 mouse (Doonan et al., 2011 J. Neurochem 118:915-27). A good therapeutic candidate should not only prevent photoreceptor cell death, but also limit retinal cytoarchitecture disruption and synaptic connectivity impairment. Our aim was to evaluate norgestrel efficacy on these parameters.
Animals were treated in accordance to the ARVO statement for the use of animals in ophthalmic and vision research. Norgestrel or the vehicle only as a control was administered intraperitoneally to rd10 mice (100 mg/kg) on alternate days, commencing on postnatal day (P)18. Mice were sacrificed on P40 and the retinal tissue was processed for immunohistochemistry. Vertical cryosections were stained with antibodies specific for photoreceptor, horizontal and bipolar cell markers, and visualized by confocal microscopy. In addition, preservation of synaptic contacts at the outer plexiform layer was evaluated.
Immunostaining with gamma-transducin showed relatively good preservation of cone photoreceptor morphology up to P40, especially in the peripheral retina. Calbindin, GNB3 and PKC-alpha labeling revealed improved horizontal and bipolar cell morphology in norgestrel-treated animals. Retinas from norgestrel-treated rd10 mice also exhibited stronger immunoreactivity for the synaptic ribbon components CtBP2 and bassoon, and the synaptic vesicle glycoprotein synaptophysin, when compared to vehicle-treated animals.
Our results confirm the previously described neuroprotective effects of norgestrel on retinal degeneration. Further, we demonstrate that norgestrel delays retinal remodeling and loss of synaptic contacts associated with photoreceptor degeneration, indicating it may be a good therapeutic candidate for the treatment of retinitis pigmentosa and related diseases.
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