Light Damage in the Rat Retina: Effect of a Radioprotective Agent (Wr‐77913) on Acute Rod Outer Segment Disk Disruptions

Remé, Charlotte E.; U, Braschler; Roberts, Joan E.; Dillon, James

doi:10.1111/j.1751-1097.1991.tb01997.x

Cited by 41 publications

(23 citation statements)

References 22 publications

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“…Constant light produces a shortening of the outer segments of about 68%, but Naftidrofuryl had no protective effect on the segment lengths in any case. Thus, Naftidrofuryl protects the numbers of photoreceptors but not their integrity, despite the fact that we have not investigated if it acts on the regeneration of these segments in the long-term as has been demonstrated for other radical scavengers (13). It acts more as a survival component than as a neurotrophic component, confirming the results obtained in vitro (2).…”

Section: Discussionsupporting

confidence: 71%

Protection Against Light-Induced Retinal Degeneration with Naftidrofuryl (Praxilene) in the Rat

Safars

Jeanny²,

Mosnier³

et al. 1997

Journal of Ocular Pharmacology and Therapeutics

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The purpose of this work was to investigate the ability of Naftidrofuryl (Praxilene, Lipha-Santé, France) to produce light-induced retinal degeneration in the rat. Fisher male rats were injected intraperitoneally with 30 mg/kg Naftidrofuryl in 0.9% NaCl. The first injection took place 30 minutes before the beginning of the constant light exposure (90 fc) and was repeated at days 2 and 4. The animals were sacrificed at day 7. Controls treated or not with Naftidrofuryl were exposed to a regular cyclic light environment (20 fc). Eyes were fixed in 4% paraformaldehyde and embedded in Historesin. Whole median 5 microns sections of the retina were analyzed by measurement of the thickness of the retinal photoreceptor nuclear and inner and outer segment layers with a Biocom image analyzer. After one week of constant illumination, the photoreceptor nuclear layer thickness decreased in all regions of the retina, more in the superior than in the inferior region. In animals treated with Naftidrofuryl, a significant rescue from degeneration was observed throughout all retinal regions. An average rescue of 66% (compared with the retina from constantly illuminated rats) was observed. Naftidrofuryl had no effect on cyclic light-raised rats. Naftidrofuryl partially protects against the degeneration of photoreceptors induced by constant light illumination of the rat retina.

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Section: Discussionsupporting

confidence: 71%

Protection Against Light-Induced Retinal Degeneration with Naftidrofuryl (Praxilene) in the Rat

Safars

Jeanny²,

Mosnier³

et al. 1997

Journal of Ocular Pharmacology and Therapeutics

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“…27,48,49 This creates a stressful environment, with the metabolic byproducts that are formed, primarily reactive oxygen species, constantly attacking neuroretinal DNA. 27,50,51 Like the rest of the central nervous system, the retina depends on glia, mostly Muller cells and astrocytes, for proper function. We have discovered that the pathological appearance of astrocytes along the retinal blood vessel may result in microhemorrhage incidents.…”

Section: Discussionmentioning

confidence: 99%

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

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Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atmdeficient mice (Atm ؊/؊ ). At 2 months of age, angiography revealed faint retinal vasculature in Atm ؊/؊ animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm ؊/؊ retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Some brain disorders may have a vascular origin, 1,2 and vascular diseases can be directly linked to neuronal and synaptic dysfunction through changes in the blood flow, increase in blood-brain barrier permeability, and in nutrient supply. 3 A healthy brain relies on the proper function and communication of all cells comprising the neurovascular unit: neurons, astrocytes, brain endothelium, and vascular smooth muscle cells. 4 Impaired genomic stability interferes with cellular homeostasis and poses a constant threat to cellular viability. 5 The cell combats this threat by activating the DNA damage response (DDR), a complex signaling network that detects the DNA lesions, promotes their repair, and temporarily modulates cellular metabolism while the damage is being repaired. 6 The DDR is vigorously activated by DNA double-strand breaks (DSBs), a particularly cytotoxic DNA lesion induced by ionizing radiation, radiomimetic chemicals, and oxygen radicals. 7,8 The DNA damage response is a hierarchical process executed by sensor/mediator proteins that accumulate at DSB sites and by protein kinases that serve as transducers of the DNA damage alarm to numerous downstream effectors. 6 The primary transducer of the cellular response to DSBs is the protein kinase ATM, which phosphorylates many key players in the various branches of the DDR. 9 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene that encodes the ATM protein. 10 A-T is characterized by progressive neurodegeneration affecting mainly the cerebellum, which develops into severe neuromotor dysfunction;

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“…All-trans-retinal and the Gradient of Photodamage along the OS-In both rats and monkeys, acute exposure to broad spectrum visible light produces a disorganization of photoreceptor OSs that is most prominent in the distal region of the OS where the discs are oldest (34,86,87). Assuming that photooxidative damage via all-trans-retinal represents one of the mechanisms of this damage, we suggest that this spatial pattern could reflect the following several factors either singly or in combination: (a) an intrinsic vulnerability of older discs perhaps related to the cumulative effect of previous photodamage; (b) the proximity to the choroidal blood supply, which produces an oxygen concentration gradient such that the distal OS is at a pO 2 of ϳ100 mm of mercury (equivalent to arterial blood), whereas the proximal OS is at a pO 2 of ϳ10 mm of mercury in the dark and ϳ30 mm of mercury in the light as a result of its proximity to the mitochondria-rich inner segment, the principal region of oxygen consumption within the retina (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although the identities of the biologically significant molecular targets of photodamage are not yet known, the mechanisms by which they are damaged have been inferred from experiments in which damage to the retina is abrogated when an antioxidant or free radical scavenger is administered prior to light exposure (33,34). These experiments indicate that photooxidative mechanisms play a significant role in the generation of light damage.…”

mentioning

confidence: 96%

ABCR, the ATP-binding Cassette Transporter Responsible for Stargardt Macular Dystrophy, Is an Efficient Target of All-trans-retinal-mediated Photooxidative Damage in Vitro

Sun

Nathans

2001

Journal of Biological Chemistry

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A large body of experimental and clinical data have documented the damaging effects of light exposure on photoreceptor cells although the identities of the biologically relevant molecular targets of photodamage are still uncertain. Several lines of evidence point to retinoids or retinoid derivatives as chromophores that can mediate light damage. We report here that ABCR, a photoreceptor-specific transporter involved in the recycling of all-trans-retinal, is unusually sensitive to photooxidation damage mediated by all-trans-retinal in vitro. Partial loss of ABCR function is responsible for Stargardt macular dystrophy, which is associated with accumulation of A2E, a diretinoid adduct within the retinal pigment epithelium. Photodamage to ABCR causes it to aggregate in SDS gels and results in the loss of retinal-stimulated ATPase activity. Peripherin/RDS and ROM-1, two structural proteins that colocalize with ABCR at the outer segment disc rim, are also significantly more susceptible to all-trans-retinal-mediated photodamage than are the major proteins from the rod outer segment. These observations imply that there may be specific protein targets of photodamage within the outer segment, and they may be especially relevant to assessing the risk of light exposure in those individuals who already have diminished ABCR activity due to mutation in one or both copies of the ABCR gene.

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Light Damage in the Rat Retina: Effect of a Radioprotective Agent (Wr‐77913) on Acute Rod Outer Segment Disk Disruptions

Cited by 41 publications

References 22 publications

Protection Against Light-Induced Retinal Degeneration with Naftidrofuryl (Praxilene) in the Rat

Protection Against Light-Induced Retinal Degeneration with Naftidrofuryl (Praxilene) in the Rat

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

ABCR, the ATP-binding Cassette Transporter Responsible for Stargardt Macular Dystrophy, Is an Efficient Target of All-trans-retinal-mediated Photooxidative Damage in Vitro

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