Retinal photodamage

Boulton, Mike; Różanowska, Malgorzata Barbara; Rozanowski, Bartosz

doi:10.1016/s1011-1344(01)00227-5

Cited by 331 publications

(282 citation statements)

References 141 publications

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“…Since rhodopsin is, by far, the dominant green-absorbing molecule in the albino rat retina and the action spectrum of retinal light damage corresponds to the absorption spectrum of rhodopsin (see Organisciak and Winkler, 1994, and references cited therein), the light-induced exacerbation of the SLOS rat retinal degeneration likely is rhodopsin-mediated. Hence, in agreement with current models implicating lipid peroxidation in the mechanism of retinal light damage (Wenzel et al, 2005;Glickman, 2002;Boulton et al, 2001;Organisciak and Winkler, 1994), we speculate that light absorption by rhodopsin triggers the formation of pro-oxidants, which cause oxidation of 7DHC to cytotoxic oxysterols. Since 7DHC is appreciably absent from normal retinas, this explains the hypersensitivity to retinal light damage observed in the SLOS rat model compared to normal albino rats.…”

Section: Discussionsupporting

confidence: 91%

“…6-week-old; hence, these findings are comparable to those previously observed in 4-week-old AY9944-treated rats (Fliesler et al, 1999), but are unlike those observed in 10-week-old AY9944-treated rats (Fliesler et al, 2004), where retinal degeneration was observed. As expected, photoreceptor loss from CE rat retinas was modest, with severe cellular damage and loss being relatively restricted geographically to the superior central region, in complete agreement with the prior findings of several other labs (see Wenzel et al, 2005;Glickman, 2002;Boulton et al, 2001;Organisciak and Winkler, 1994). Retinal histology in the inferior central zone and in the peripheral retina of both hemispheres appeared relatively normal.…”

Section: Histology and Quantitative Morphometrysupporting

confidence: 89%

“…In normal albino rats, under the conditions employed in this study (1700 lx, 490-580 nm light, 24 hr exposure following 24-hr dark adaptation), photoreceptor cell death and loss are largely localized to the superior central retina (Wenzel et al, 2005;Glickman, 2002;Boulton et al, 2001;Organisciak and Winkler, 1994). However, in AY9944-treated albino rats, the zone of photoreceptor death and loss extends to the mid-peripheral retina in both the superior and inferior hemispheres, with essentially total loss of photoreceptors in the central zone.…”

Section: Discussionmentioning

confidence: 98%

“…Retinal light damage involves oxidative modification of endogenous retinal lipids, proteins, and nucleic acids (Wenzel et al, 2005;Glickman, 2002;Boulton et al, 2001;Organisciak and Winkler, 1994). Genetic or environmental conditions that lead to an increase in reactive oxygen species or oxidation-prone target molecules would be expected to increase both oxidative stress and cytotoxic reactions.…”

Section: Introductionmentioning

confidence: 99%

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Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

Vaughan

Peachey

Richards

et al. 2006

Experimental Eye Research

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Potentiation of retinal degeneration by intense light exposure, and its amelioration by an antioxidant, were studied in a rat model of Smith-Lemli-Opitz syndrome (SLOS), in comparison with normal (control) Sprague-Dawley rats. The SLOS model is created by treating rats with AY9944, a selective inhibitor of cholesterol synthesis at the level of 3β-hydroxysterol-Δ 7 -reductase. A subset of rats was treated with dimethylthiourea (DMTU), a synthetic antioxidant, 24 and 1 hr prior to light exposure. Half of the animals (±DMTU) were exposed to intense, constant, green light (24 hr, 1700 lx, 490-580 nm), while the others were maintained in darkness. Subsequently all animals were returned to dim cyclic light (20-40 lx, 12 hr light-12 hr dark) for 2 weeks, after which electroretinograms were recorded. One eye from each rat was taken for histological and quantitative morphometric analyses; sterol analysis was performed on retinas from contralateral eyes. HPLC analysis confirmed the accumulation of 7-dehydrocholesterol (7DHC) in retinas of AY9944-treated rats; cholesterol represented >99% of the sterol in control retinas. Histology of retinas from unexposed, AY9944-treated rats (6-week-old) was normal. In contrast, age-matched, light-exposed rats exhibited massive photoreceptor cell loss in both the superior and inferior hemispheres, and concomitant rod and cone dysfunction. The severity and geographic extent of the damage was far greater than that observed in normal albino rats exposed to the same conditions. DMTU pre-treatment largely prevented these degenerative changes. These findings indicate that the AY9944-induced rat SLOS model is hypersensitive to intense light-induced retinal damage, relative to normal rats. DMTU protection against light-induced damage implicates free radical-based oxidation in the retinal degeneration process. Furthermore, the use of green light (corresponding to the absorption maxima of rhodopsin) implicates rhodopsin in the initiation of the pathobiological mechanism. We propose that generation of cytotoxic oxysterols (by-products of 7DHC oxidation) is an integral part of retinal cell death in the SLOS rat model, which is exacerbated by intense light. Furthermore, the results predict lightdependent potentiation of retinal degeneration in SLOS patients, and the possible ameliorative effects of antioxidant therapy.

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Section: Discussionsupporting

confidence: 91%

Section: Histology and Quantitative Morphometrysupporting

confidence: 89%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

Vaughan

Peachey

Richards

et al. 2006

Experimental Eye Research

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“…These results show that inhibition of the chymotrypsin-like activity can critically affect cell survival under stressful conditions. Considering that the retina in vivo is particularly prone to oxidative stress due to the high oxygen tension and metabolic activity as well as the presence of photosensitive pigments that generate reactive oxygen species (Boulton et al, 2001), it is possible that this tissue periodically experiences sufficient stress to surpass a threshold for maintaining cellular redox homeostasis. Therefore, the loss in chymotrypsin-like activity in aged retina could result in reduced tolerance of oxidative stress via several mechanisms, including the decreased clearance of oxidatively damaged proteins.…”

Section: Consequences Of Proteasome Inhibitionmentioning

confidence: 99%

Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina

Kapphahn

Bigelow

Ferrington

2007

Experimental Eye Research

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The proteasome plays a fundamental role in processes essential for cell viability. A loss in proteasome function has been associated with aging, as well as a number of age-related diseases. Defining the mechanism(s) behind this loss in function will add important information regarding the molecular basis for aging. In the current study, we performed an age-based comparison of proteasome function and composition of subunits and regulatory proteins in the neural retina and retinal pigment epithelium (RPE) in Fischer 344 rats. In the RPE, there was no age-dependent difference in activity, subunit composition, or content of proteasome regulators, PA28 and PA700. In contrast, the aged neural retina demonstrated a significant reduction in the chymotrypsin-like activity and decreased degradation of both casein and casein modified by 4-hydroxynonenal. This loss in function could not be explained by differences in subunit composition, content of PA28 and PA700, or reversible modification of cysteine residues. To begin investigating the molecular basis for the age-associated decrement in proteasome function, we modified the cysteine residues in proteasome from young rats with the sulfhydryl reactive chemical N-ethylmaleimide. We observed inhibition of the chymotrypsin-like activity and decreased degradation of casein that was comparable to that seen in aged retinas. Thus, chemical modification of cysteine provides an in vitro method that partially recapitulates aging proteasome. Further studies are required to confirm irreversible modification of functionally significant cysteine as a potential mechanism behind the age-related loss in proteasome function.

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Retinal Degeneration in a Rodent Model of Smith-Lemli-Opitz Syndrome

et al. 2004

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Objective: To assess the electrophysiologic, histologic, and biochemical features of an animal model of Smith-Lemli-Opitz syndrome (SLOS).Methods: Sprague-Dawley rats were treated with AY9944, a selective inhibitor of 3␤-hydroxysterol-⌬ 7reductase (the affected enzyme in SLOS). Dark-and lightadapted electroretinograms were obtained from treated and control animals. From each animal, 1 retina was analyzed by microscopy, and the contralateral retina plus serum samples were analyzed for sterol composition. The main outcome measures were rod and cone electroretinographic amplitudes and implicit times, outer nuclear layer (ONL) thickness, rod outer segment length, pyknotic ONL nucleus counts, and the 7-dehydrocholesterol/ cholesterol mole ratio in the retina and serum.Results: By 10 weeks' postnatal age, rod and cone electroretinographic wave amplitudes in AY9944-treated animals were significantly reduced and implicit times were significantly increased relative to controls. Maximal rod photoresponse and gain values were reduced approximately 2-fold in treated animals relative to controls. The ONL thickness and average rod outer segment length were reduced by approximately 18% and 33%, respectively, and ONL pyknotic nucleus counts were approximately 4.5-fold greater in treated animals relative to controls. The retinal pigment epithelium of treated animals contained massive amounts of membranous/lipid inclusions not routinely observed in controls. The 7-dehydrocholesterol/cholesterol mole ratios in treated retinas and serum samples were approximately 5:1 and 9:1, respectively, whereas the ratios in control tissues were essentially zero.Conclusions: This rodent model exhibits the key biochemical hallmarks associated with SLOS and displays electrophysiologic deficits comparable to or greater than those observed in the human disease.Clinical Relevance: These results predict retinal degeneration in patients with SLOS, particularly those with the more severe (type II) form of the disease, and may be more broadly relevant to other inborn errors of cholesterol biosynthesis. This animal model may also be of use in evaluating therapeutic treatments for SLOS and in understanding the slow phototransduction kinetics observed in patients with SLOS.

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Retinal photodamage

Cited by 331 publications

References 141 publications

Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina

Retinal Degeneration in a Rodent Model of Smith-Lemli-Opitz Syndrome

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