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...

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.

Oxidative and nitrosative damage are major contributors to cone cell death in retinitis pigmentosa (RP). In this study, we explored the effects of augmenting components of the endogenous antioxidant defense system in models of RP, rd1 and rd10 mice. Unexpectedly, over-expression of superoxide dismutase 1 (SOD1) in rd1 mice increased oxidative damage and accelerated cone cell death. With an elaborate mating scheme, genetically engineered rd10 mice with inducible expression of SOD2, Catalase, or both in photoreceptor mitochondria were generated. Littermates with the same genetic background that did not have increased expression of SOD2 nor Catalase provided ideal controls. Co-expression of SOD2 and Catalase, but not either alone, significantly reduced oxidative damage in the retinas of postnatal day (P) 50 rd10 mice as measured by protein carbonyl content. Cone density was significantly greater in P50 rd10 mice with co-expression of SOD2 and Catalase than rd10 mice that expressed neither, or SOD2 or Catalase alone. Co-expression of SOD2 and Catalase in rd10 mice did not slow rod cell death. These data support the concept of bolstering the endogenous antioxidant defense system as a gene-based treatment strategy for RP, but also indicate that co-expression of multiple components may be needed.