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.

Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

“…45,46 MFP also antagonizes progesterone receptors, 47 which are also involved in Bcl-X L upregulation 48,49 and have a role in photoreceptor protection. 50,51 Our present findings, however, suggest that glucocorticoid signaling is required for photoreceptor survival. We used male mice, where progesterone levels are low, 52 and survival was promoted by DEX, a selective ligand of GRa, with very low affinity for mineralocorticoid and progesterone receptors.…”

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

“…The paucity of effective treatments for blinding retinal diseases, coupled with information about new therapeutic targets, has prompted intense investigation of innovative strategies to combat debilitating retinopathies. The rd10 mouse has proven quite informative in this regard (39,46,(53)(54)(55)(56). Our findings that the activation of Sig1R has powerful neuroprotective effects in this murine model are extremely encouraging.…”

Norgestrel may be a potential therapy for retinal degenerations

“…However, our recent study involving i.p. administration of norgestrel (100 mg/kg) showed significant protection of mouse photoreceptor cells in both a light-induced and an inherited retinal degeneration model [14]. Clearly, a higher concentration of norgestrel is used which could contribute to the positive results described.…”