Retinitis pigmentosa (RP) is a group of inherited retinopathies characterized by progressive photoreceptor death. Retinitis pigmentosa is a rare and inherited degenerative disease that causes loss of vision due to the death of photoreceptors in the retina and for which there is currently no treatment. RP accounts for about half of all inherited retinal disease cases worldwide. In this condition, rods typically die through mutation-related mechanisms and, subsequently, retinal cones degenerate more slowly in other ways. Although more than 100 genes have now been linked to RP, the exact mechanisms underlying this retinal degeneration leading to photoreceptor death are incomplete. In fact, although some changes in the retina result as a direct mutation effect, some other changes result from changes in gene expression.
Safe data suggest oxidative stress and local inflammatory responses increase with the progression of the disease. This contributes to the remodeling of the retina. The research group of the Cardenal Herrera University on therapeutic strategies for ocular pathologies, led by Professor María Miranda Sanz, studies the biological mechanisms of RP and has already tested in the past the effectiveness of progesterone in preventing the death of photoreceptors in this disease. A few years ago, in support of the intervention of oxidative stress in its pathogenesis, her team demonstrated a greater protective effect of progesterone when combined with a vitamin-like compound that is also a powerful antioxidant: lipoic acid. It is also considered an anti-inflammatory, capable of reducing oxidative stress in the retina, as it can regenerate intracellular glutathione (GSH), the body’s main antioxidant.
Lipoic acid has also been shown to be useful in eye diseases, such as glaucoma, diabetic retinopathy, and cataracts. But the role of other internal hormones can also safeguard the health of the photoreceptors in the retina. Professor Sanz’s group more recently showed that cortisol receptors can also affect the health of these cells. When the RP retina is irradiated with light in the presence of progesterone receptor agonists (mifepristone), they die at a doubling rate. At high doses, however, mifepristone is also an antagonist of cortisol receptors (GR). But if they are given progesterone and a glucocorticoid agonist (dexamethasone), nearly 90% of diseased RP cells are preserved from direct light damage. As a cellular protection mechanism, progesterone does another clever thing: it changes the expression of the GR receptors, reducing the alpha form and increasing the beta form, which has a lower affinity for cortisol.
The very latest studies on the subject of this research group have further proved that by applying progesterone at the ocular level in RDS mice (a model of genetic retinopathy), the loss of life in these animals can be slowed. And the mechanism is twofold: the hormone not only protects the photoreceptors but also reduces the local infiltration of the microglia, the immune cells of the brain. So it also acts as an anti-inflammatory. The effects are more evident if you act in the early stages of the disorder. Unlike oral administration, ocular administration of progesterone eliminates the passage of its metabolism in the liver, which in the case of progesterone is quite extensive, thus allowing the use of smaller doses and increasing its effectiveness. No additional antioxidant compounds such as lipoic acid have been investigated. But its integration in retinopathies (alone or with progesterone) is desirable for several reasons.
Among these, the first of all because it is safe (as mentioned before it is a vitamin cofactor), it is cheap and it is fat-soluble, that is, it passes the lipid structures of the brain and penetrates the brain within minutes. The need to find effective and safe solutions for PR is a priority, considering that at least one and a half million people in the world are affected.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Advised in this website
Retinopath(ies) reclaimed: oxidative stress and bad lipids as wicked weeds to uproot (23/03/2022)
Scientific references
Alambiaga-Caravaca AM et al. Pharmaceuticals. 2022; 15(3):328.
Benlloch-Navarro S et al. J Steroid Biochem Mol Biol. 2019; 189:291.
Ramirez-Lamelas T et al. Front Pharmacol. 2018 May 9; 9:469.
Sánchez-Vallejo V et al. Pharmacol Res. 2015 Sep; 99:276-88.
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