Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration

Wenzel, Andreas; Grimm, Christian; Samardzija, Marijana; Remé, Charlotte E.

doi:10.1016/j.preteyeres.2004.08.002

Cited by 578 publications

(559 citation statements)

References 209 publications

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“…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: 90%

“…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: 97%

“…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: Histology and Quantitative Morphometrysupporting

confidence: 90%

Section: Discussionmentioning

confidence: 97%

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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“…However, to date the role of cathepsins in retinal cell death has received little attention. For instance, an up-regulation in the expression of cathepsins has been detected during photoreceptor degeneration in mutant animals (Sharma and Rohrer, 2004;Doonan et al, 2005;Wenzel et al, 2005;Lohr et al, 2006) and in retinal cells after optic nerve transection and optic nerve crush (Agudo et al, 2009). Moreover, cathepsins B and L are involved in retinal cell death induced by growth factor deprivation in the embryonic mouse retina (Valenciano et al, 2006).…”

Section: Spatiotemporal Expression Of Cathepsin B and D Genes: Relatimentioning

confidence: 99%

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

Bejarano-Escobar

Holguín-Arévalo

Montero

et al. 2011

Developmental Dynamics

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Here, we show a detailed chronotopographical analysis of cathepsin B and D expression during development of the mouse visual system. Both proteases were detected in large rounded/ameboid cells usually located in close relationship with prominent sites of extensive physiological cell death. In concordance with their morphological features and topographical distribution, we demonstrate that expressing cells corresponded with macrophages and microglial precursors. We found that as microglial precursors differentiated the expression of both cathepsins was down-regulated. Of interest, cathepsin B and D transcripts were never observed in degenerating cells. Our findings point to a role for cathepsin D and B in cell debris degradation after apoptotic processes rather than promoting cell death, as proposed for other developmental models. Additionally their pattern of expression suggests a role in the maturation of the microglial precursors.

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“…To study signaling pathways and molecular mechanisms during the degenerative processes, several mouse models of inherited retinal degeneration are used (Fauser et al 2002). These models are complemented by models of induced photoreceptor apoptosis like the model of light-induced degeneration (Wenzel et al 2005). The advantage of the induced models is the synchronized apoptotic response of many photoreceptor cells to the death stimulus.…”

Section: Introductionmentioning

confidence: 99%

The Hypoxic Transcriptome of the Retina: Identification of Factors with Potential Neuroprotective Activity

Thiersch

Raffelsberger

Frigg

et al. 2008

Advances in Experimental Medicine and Biology

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Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration

Cited by 578 publications

References 209 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

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

The Hypoxic Transcriptome of the Retina: Identification of Factors with Potential Neuroprotective Activity

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