Inherited Retinal Dystrophies: Role of Oxidative Stress and Inflammation in Their Physiopathology and Therapeutic Implications

Abstract

Inherited retinal dystrophies (IRDs) are a large group of genetically and clinically heterogeneous diseases characterized by the progressive degeneration of the retina, ultimately leading to loss of visual function. Oxidative stress and inflammation play fundamental roles in the physiopathology of these diseases. Photoreceptor cell death induces an inflammatory state in the retina. The activation of several molecular pathways triggers different cellular responses to injury, including the activation of microglia to eliminate debris and recruit inflammatory cells from circulation. Therapeutical options for IRDs are currently limited, although a small number of patients have been successfully treated by gene therapy. Many other therapeutic strategies are being pursued to mitigate the deleterious effects of IRDs associated with oxidative metabolism and/or inflammation, including inhibiting reactive oxygen species’ accumulation and inflammatory responses, and blocking autophagy. Several compounds are being tested in clinical trials, generating great expectations for their implementation. The present review discusses the main death mechanisms that occur in IRDs and the latest therapies that are under investigation.

Systemic taurine treatment affords functional and morphological neuroprotection of photoreceptors and restores retinal pigment epithelium function in RCS rats

“…We also document using immunohistochemistry to 8-OHdG that taurine treatment decreases oxidative damage in the ONL and INL of the RCS rat retina. Oxidative stress has an important pathogenic potential in neurodegenerative diseases such as RP [ 66 ], being one of the main contributors to photoreceptor death [ 66 , 75 ]. Taurine is a well-known antioxidant [ 20 , 33 ] and its neuroprotective effects may be mediated through its antioxidant effects [ [20] , [33] , [38] ].…”

Polyunsaturated Lipids in the Light-Exposed and Prooxidant Retinal Environment

“…The oxygen gradient along rod OS (see Figure 2 above) and the high DHA content, both have implications for oxidative stress (recently reviewed in [ 59 ]) affecting OS lipids and photoreceptor damage [ 60 ]. An element to consider in oxidative stress involving photoreceptors and RPE cells is that these cells are exposed to blue light (range 400–480 nm), which may induce oxidative stress [ 61 , 62 ] (reviewed in [ 63 ]) via multiple mechanisms (reviewed by [ 64 , 65 ]).…”

Cellular and molecular alterations in neurons and glial cells in inherited retinal degeneration

“…Neuronal death in degenerative diseases is traditionally related to apoptosis; however, there is strong evidence that photoreceptor death is not exclusively directed by apoptosis in retinal dystrophies, and alternative non-apoptotic cell death pathways prevail ( Sancho-Pelluz et al, 2008 ; Arango-Gonzalez et al, 2014 ; Pinilla et al, 2022 ). Hence, a wide range of apoptotic and non-apoptotic death mechanisms are activated in almost all IRDs that affect photoreceptor cells, including parthanatos, calpain-dependent cell death, or ferroptosis, among others.…”