Oxidative damage is a potential cause of cone cell death in retinitis pigmentosa

Shen, Jikui; Yang, Xinmin; Dong, Aling; Petters, Robert M.; Peng, Yuandong; Wong, Fulton; Campochiaro, Peter A.

doi:10.1002/jcp.20346

Cited by 265 publications

(255 citation statements)

References 39 publications

Supporting

Mentioning

246

Contrasting

Unclassified

Order By: Relevance

“…Using oxygen electrodes, it has been shown that oxygen levels are significantly increased in the outer retina after rods degenerate (5). We have also shown in a transgenic pig model of RP that after disappearance of rods, there is progressive oxidative damage in cones during the period when cones are dying (12). In this study, we showed that in the rd1 mouse model of RP, staining for acrolein, a marker for oxidative damage to lipids, is not detectable in cones at P18 when rod degeneration is just being completed, but by P35, Ϸ2 weeks after the disappearance of most rods and in midst of cone cell death, remaining cones stain for acrolein.…”

Section: Discussionmentioning

confidence: 99%

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Komeima

Rogers

Lü³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

372

367

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Komeima

Rogers

Lü³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

372

367

View full text Add to dashboard Cite

show abstract

“…This article is a PNAS Direct Submission. 1 To whom correspondence should be addressed. E-mail: xi-qin-ding@ouhsc.edu.…”

Section: Significancementioning

confidence: 99%

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Thapa

Morris

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunitdeficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotidegated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.R od and cone photoreceptors degenerate under a variety of pathological conditions, including a wide array of hereditary retinal diseases, such as retinitis pigmentosa, macular degeneration, and cone-rod dystrophies. Defects in a large number of genes are linked to inherited retinal degenerative disorders (www.sph. uth.tmc.edu/RetNet/disease.htm), including those encoding enzymes involved in the recycling of 11-cis retinal in the retinal pigment epithelium (RPE), retinoid isomerase (RPE65), and lecithin retinol acyltransferase (LRAT), and the phototransductionassociated proteins (opsins, subunits of transducin, cGMP phosphodiesterase PDE6, guanylate cyclase, and cyclic nucleotidegated channel). There are currently no treatments for human retinal dystrophies. Despite a high genetic heterogeneity, the degenerating photoreceptors show common cellular disorder features, including oxidative damage (1, 2), endoplasmic reticulum stress (3, 4), and apoptosis (5, 6).Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. The role of TH signaling in retina regarding its regulation of cone opsin expression and patterning has been well documented (7,8). Most mammals possess dichromatic color vision that is mediated by two opsins with peak sensitivities to medium-long ...

show abstract

“…As mentioned above, oxidative stress has been suggested as one of the causes of cone dysfunction and death in RP (Yu et al, 2004;Shen et al, 2005;Komeima et al, 2006). As the rods die in RP, the flow of oxygen from the choroidal circulation does not abate, and thus each cone is exposed to increasing amounts of oxygen (Yu et al, 2000(Yu et al, , 2004.…”

Section: Treatment With Antioxidantsmentioning

confidence: 99%

“…However, cone death often does not occur until many months after rod death (Carter-Dawson et al, 1978;Milam et al, 1998;Berson, 2008;Lin et al, 2009;Punzo et al, 2009). Another model holds that there is an increase in oxidative damage to cones once the rods have died (Yu et al, 2004;Shen et al, 2005;Komeima et al, 2006). This model also suggests a therapy, that is, delivery of antioxidants or genes encoding antioxidation enzymes.…”

Section: Overview Of Therapeutic Approaches To Rpmentioning

confidence: 99%

“…As the rods die in RP, the flow of oxygen from the choroidal circulation does not abate, and thus each cone is exposed to increasing amounts of oxygen (Yu et al, 2000(Yu et al, , 2004. Studies of the levels of oxidized proteins, nucleic acids, and lipids have shown that oxidative damage increases during the course of RP (Shen et al, 2005;Komeima et al, 2006). Oxidative stress is likely not only correlated with photoreceptor degeneration in RP, but contributes to it.…”

Section: Treatment With Antioxidantsmentioning

confidence: 99%

See 1 more Smart Citation