Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones. The mechanism of cone cell death is uncertain. Rods are a major source of oxygen utilization in the retina and, after rods die, the level of oxygen in the outer retina is increased. In this study, we used the rd1 mouse model of RP to test the hypothesis that cones die from oxidative damage. A mixture of antioxidants was selected to try to maximize protection against oxidative damage achievable by exogenous supplements; ␣-tocopherol (200 mg͞kg), ascorbic acid (250 mg͞kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg͞kg), and ␣-lipoic acid (100 mg͞kg). Mice were treated with daily injections of the mixture or each component alone between postnatal day (P)18 and P35. Between P18 and P35, there was an increase in two biomarkers of oxidative damage, carbonyl adducts measured by ELISA and immunohistochemical staining for acrolein, in the retinas of rd1 mice. The staining for acrolein in remaining cones at P35 was eliminated in antioxidant-treated rd1 mice, confirming that the treatment markedly reduced oxidative damage in cones; this was accompanied by a 2-fold increase in cone cell density and a 50% increase in medium-wavelength cone opsin mRNA. Antioxidants also caused some preservation of cone function based upon photopic electroretinograms. These data support the hypothesis that gradual cone cell death after rod cell death in RP is due to oxidative damage, and that antioxidant therapy may provide benefit. oxidative damage ͉ photoreceptors ͉ retinal degenerations R etinitis pigmentosa (RP) refers to a group of diseases in which a mutation results in death of rod photoreceptors followed by gradual death of cones. The diseases referred to as RP show a similar phenotype consisting of pigmented spots scattered throughout the retina, narrowed retinal vessels, and retinal sheen suggesting atrophy. At one time, it was felt that inflammation was important in the pathogenesis, and hence the term ''retinitis'' was paired with a descriptor for the most prominent feature of the phenotype, the scattered pigment, resulting in the term retinitis pigmentosa. It is now known that this phenotype results whenever there is widespread rod photoreceptor cell death. Although toxins or infections can occasionally cause widespread rod death, it occurs most commonly when there is a mutation in a gene that is selectively expressed in rods and, either through gain or loss of function, the mutation promotes rod cell death. Mutations in 36 different genes have been found to cause RP, and mutations in many more cause widespread rod cell death in association with syndromes that have extraocular manifestations (www.sph.uth.tmc.edu͞RetNet͞ sum-dis.htm).How does diffuse death of rods throughout the retina result in the distinctive phenotype that ophthalmologists recognize as RP? Rods have an intimate relationship, both structurally and functionally, with retinal pigmen...

Seeing the light: New insights into the molecular pathogenesis of retinal diseases

“…Using a transgenic pig model of RP and immunohistochemical markers for oxidative damage, the hypothesis that cones undergo progressive oxidative damage after the death of rods was tested and found to be correct . In rd1 mice, it was found that daily administration of a mixture of antioxidants was able to substantially ameliorate oxidative damage after death of rods and significantly reduced cone cell death (Komeima et al, 2006). Similar findings were obtained in the Q344ter mouse model of ADRP and rd10 mice, a model of more slowly progressive autosomal recessive RP.…”

Receptor interacting protein kinase mediates necrotic cone but not rod cell death in a mouse model of inherited degeneration

“…On the other hand, RIP1 forms a complex with NADPH oxidase 1 and TNF-R1-associated death domain and produces superoxide, which in turn leads to induction of necrosis (41). In animal models of RP, Campochiaro and colleagues have demonstrated that retinal oxidative stress increases especially in the period of cone degeneration and that antioxidant treatments delay cone cell death (28,40).…”

“…The mechanisms of cone cell death in RP are less well characterized. Although loss of rodderived trophic factors (27), oxidative stress (28), and nutrient starvation (29) are shown to contribute to the cone degeneration, little is known about the cell death types and molecules that mediate cone cell death.…”

The Thioredoxin-like Protein Rod-derived Cone Viability Factor (RdCVFL) Interacts with TAU and Inhibits Its Phosphorylation in the Retina

“…After rods die, oxygen consumption in the outer retina is markedly reduced, and tissue oxygen levels become substantially elevated (6). This results in progressive oxidative damage to cones and gradual cone cell death, which can be slowed by antioxidants (7). The antioxidant defenses include vitamins, minerals, and the antioxidant enzymes glutathione, superoxide dismutase, hydrogen peroxidase, catalase, and thioredoxins (8).…”