title: Enhancing survival of photoreceptor cells in vivo using the synthetic progestin Norgestrel.
abstract: Retinal degenerations such as Retinitis Pigmentosa remain difficult to treat given the diverse array of genes responsible for their aetiology. Rather than concentrate on specific genes, our focus is on identifying therapeutic avenues for the treatment of retinal disease that target general survival mechanisms or pathways. Norgestrel is a synthetic progestin commonly used in hormonal contraception. Here, we report a novel anti-apoptotic role for Norgestrel in diseased mouse retinas in vivo. Dosing with Norgestrel protects photoreceptor cells from undergoing apoptosis in two distinct models of retinal degeneration; the light damage model and the Pde6b(rd10) model. Photoreceptor rescue was assessed by analysis of cell number, structural integrity and function. Improvements in cell survival of up to 70% were achieved in both disease models, indicating that apoptosis had been halted or at least delayed. A speculative mechanism of action for Norgestrel involves activation of survival pathways in the retina. Indeed, Norgestrel increases the expression of basic fibroblast growth factor which is known to both promote cell survival and inhibit apoptosis. In summary, our results demonstrate significant protection of photoreceptor cells which may be attributed to Norgestrel mediated activation of endogenous survival pathways within the retina.
authors.affiliation: Biochemistry Department, Bioscience Research Institute, University College Cork, Cork, Ireland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Doonan
authors.forename: Carolyn
authors.initials: C
authors.lastname: O'Driscoll
authors.forename: Paul
authors.initials: P
authors.lastname: Kenna
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Cotter
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004596:Electroretinography; D005346:Fibroblast Growth Factors / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D008027:Light / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009644:Norgestrel / Q000494:pharmacology* / Q000627:therapeutic use; D010786:Photoreceptor Cells / Q000187:drug effects*; D045167:Progesterone Congeners / Q000494:pharmacology / Q000627:therapeutic use; D012160:Retina / Q000166:cytology*; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D045167:Progesterone Congeners; D009644:Norgestrel; D005346:Fibroblast Growth Factors; D048052:Mitogen-Activated Protein Kinase 3