ascorbic-acid and Retinitis-Pigmentosa

Topics: Alcohols; Ascorbic Acid; Carbohydrate Metabolism; Chloroquine; Erythrocytes; Eye Diseases; Glucosephosphate Dehydrogenase Deficiency; Glucosephosphates; Glutathione; Histocytochemistry; Lens, Crystalline; Lipid Metabolism; Metabolism; Methanol; Phenothiazines; Retina; Retinal Pigments; Retinitis Pigmentosa; Toxicology; Vitamin A Deficiency

Retinitis pigmentosa (RP) is a heterogeneous group of diseases in which one of a wide variety of mutations selectively causes rod photoreceptor cell death. After rods die, cone photoreceptors gradually die resulting in blindness. Antioxidants reduce cone cell death in rd1/rd1 mice indicating that cones die from oxidative damage in that model of rapidly progressive RP. In this study, we sought to determine if this observation could be generalized to models of other types of RP, rd10/rd10 mice, a model of more slowly progressive recessive RP, and Q344ter mice, a model of rapidly progressive dominant RP. Compared to appropriate vehicle-treated controls, rd10/rd10 and Q344ter mice treated between P18 and P35 with a mixture of antioxidants previously found to be effective in rd1/rd1 mice showed significantly greater cone survival. Antioxidant-treated rd10/rd10 mice showed preservation of cone function as shown by a significant increase in photopic ERG b-wave amplitudes, and surprisingly showed temporary preservation of scotopic a-wave amplitudes, prolonged rod survival, and slowed depletion of rhodopsin mRNA. These data suggest that oxidative damage contributes to cone cell death regardless of the disease causing mutation that leads to the demise of rods, and that in more slowly progressive rod degenerations, oxidative damage may also contribute to rod cell death. Protection from oxidative damage may be a broadly applicable treatment strategy in RP.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Cell Death; Codon, Nonsense; Cyclic Nucleotide Phosphodiesterases, Type 6; Disease Models, Animal; Drug Administration Schedule; Electroretinography; Exons; Heterozygote; Homozygote; Injections, Intraperitoneal; Kinetics; Mice; Mice, Mutant Strains; Mutation, Missense; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; RNA, Messenger; Thioctic Acid

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; alpha-tocopherol (200 mg/kg), ascorbic acid (250 mg/kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg/kg), and alpha-lipoic acid (100 mg/kg). 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.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Cell Death; Disease Models, Animal; Electroretinography; Metalloporphyrins; Mice; Mice, Inbred C57BL; Oxidative Stress; Oxygen; Retina; Retinal Cone Photoreceptor Cells; Retinitis Pigmentosa; Thioctic Acid

Topics: Ascorbic Acid; Flavonoids; Folic Acid; Nutrition Therapy; Papaverine; Retinitis Pigmentosa; Vitamin B Complex; Vitamins