Antioxidants slow photoreceptor cell death in mouse models of retinitis pigmentosa

Abstract

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.

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

“…In addition, we show that in genetically normal rod photoreceptors there is bystander cell death mediated through a caspase-dependent mechanism. Our data may provide an explanation of why using single inhibitors of cell death have had limited rescue effects and poor longterm outcomes when tested in other retinal degeneration models, 36,37 because the rod and cone photoreceptors are dying by different mechanisms so eventually all the photoreceptors are lost. The significance of our findings is that combination therapy directed at the different cell death mechanisms would be crucial in designing effective treatment strategies.…”

Blockade of neuronal nitric oxide synthase reduces cone cell death in a model of retinitis pigmentosa

“…However, the demonstration that oxidative stress is a major contributor to cone cell death provides an important therapeutic target that may apply to patients with RP regardless of the underlying mutation that starts the process [2,3]. Identifying ways to reduce damage initiated by oxidative stress in the retina is an important goal.…”

“…RP originates from one of hundreds of mutations that result in a gene product that is damaging to rods or homozygous mutations that cause lack of a protein that is needed for rod survival. The death of rods is inevitably followed by cone cell death predominantly from oxidative damage [1][2][3]. Rod photoreceptors are the most numerous cell type in the retina and the largest consumers of oxygen and after rods die, the level of oxygen in the outer retina is markedly elevated [4,5] providing the source for oxidative damage.…”

Emerging Gene Therapies for Retinal Degenerations

“…Oxidative stress is likely not only correlated with photoreceptor degeneration in RP, but contributes to it. Cone death was slowed in several mouse models of RP that were treated with exogenous antioxidants (Komeima et al, 2006(Komeima et al, , 2007. AAV delivery of endogenous antioxidant enzymes, including superoxide dismutase and glutathione peroxidase, in some RP mouse models decreased oxidative damage and prolonged cone survival Usui et al, 2009).…”