Damage to Rat Retinal DNA Induced In Vivo by Visible Light

Specht, Sandra; Leffak, Michael; Darrow, Ruth M.; Organisciak, Daniel T.

doi:10.1562/0031-8655(1999)069<0091:dtrrdi>2.3.co;2

Cited by 10 publications

(29 citation statements)

References 14 publications

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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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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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“…The action spectrum of visible-light-induced retinal damage in rats suggests that the process involves rhodopsin bleaching (6). Reactive oxygen species (ROS) † appear to be involved in visible-light-induced retinal degeneration (7)(8)(9)(10) since antioxidants such as ascorbate (11,12), the superoxide dismutase mimic 2,2,6,6-tetramethyl-4-piperidinol-N-oxyl (TEMPOL) (13) and the hydroxyl radical scavenger dimenthylthiourea (DMTU) (7,14) prevent light-induced damage to rat photoreceptors. Evidence of antioxidant protection has come from morphological analysis of retinal cells (15,16) and by quantitation of the losses in rhodopsin (11,12) or visual-cell DNA (14,17,18) from rats exposed to intense light.…”

Section: Introductionmentioning

confidence: 99%

“…Evidence of antioxidant protection has come from morphological analysis of retinal cells (15,16) and by quantitation of the losses in rhodopsin (11,12) or visual-cell DNA (14,17,18) from rats exposed to intense light. Recently, methods to monitor DNA integrity have shown prevention of light-induced DNA strand breaks in rats treated with DMTU (9,13,19,20).…”

Section: Introductionmentioning

confidence: 99%

“…The time course of DNA damage during intense light exposures of up to 24 h, including alkali-labile sites and singleor double-strand DNA breaks, suggests that visible-lightinduced damage occurs by a biphasic mechanism (9). Double-strand DNA breaks have been found in the retinas of rats exposed to 8-24 h of intense light, using in situ methods of detection and gel electrophoresis (9,19,(21)(22)(23). Antioxidant treatment revealed an early phase of ROS-mediated DNA damage, leading to a later stage of nonrandom enzymatic cleavage evidenced by the generation of nucleosome-coresized DNA fragments.…”

Section: Introductionmentioning

confidence: 99%

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Continuing Damage to Rat Retinal DNA During Darkness Following Light Exposure

Specht

Organisciak

Darrow

et al. 2000

Photochem Photobiol

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The damaging effects of visible light on the mammalian retina can be detected as functional, morphological or biochemical changes in the photoreceptor cells. Although previous studies have implicated short-lived reactive oxygen species in these processes, the termination of light exposure does not prevent continuing damage. To investigate the degenerative processes persisting during darkness following light treatment, rats were exposed to 24 h of intense visible light and the accumulation of DNA damage to restriction fragments containing opsin, insulin 1 or interleukin-6 genes was measured as single-strand breaks (ssb) on alkaline agarose gels. With longer dark treatments all three DNA fragments showed increasing DNA damage. Treatment of rats with the synthetic antioxidant dimethylthiourea prior to light exposure reduced the initial development of alkali-sensitive strand breaks and allowed significant repair of all three DNA fragments. The time course of double-strand DNA breaks was also examined in specific genes and repetitive DNA. Nucleosomal DNA laddering was evident immediately following the 24 h light treatment and increased during the subsequent dark period. The increase in the intensity of the DNA ladder pattern suggests a continuation of enzymatically mediated apoptotic processes triggered during light exposure. The protective effects of antioxidant suggests that the light-induced DNA degradative process includes both early oxidative reactions and enzymatic processes that continue after cessation of light exposure.

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“…As far as the retinal tissue is concerned, studies have demonstrated that it is particularly susceptible to oxidative damage. This is plausibly due its metabolic activity, since it contains a very high number of mitochondria and is subjected, by definition, to frequent if not continuous photo-chemical stress [15][16][17][18]. Therefore ocular nervous cells produce very high levels of radical species which, if not adequately neutralized, may cause severe damage to the hydrocarbon chains of unsaturated fatty acids, the aminoacid-residues, the nitrogen bases of nucleic acids, and carbohydrates [19].…”

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confidence: 99%

Neurodegenerative and Morpho-functional Alterations During Senescence: Positive Modulation by Lipoic Acid and Superoxide Dismutase Ocular Senescence in a Rat Model

Scarsella

Risuleo

2015

LSMR

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Abstract-We have evaluated the modulation of degenerative events at the retinal and optic nerve level in a rat model system. Degeneration was ameliorated in aging rats by the combined oral administration of -lipoic acid and superoxide dismutase. Twenty four month-old rats were fed ad libitum with a diet supplemented by these two compounds. Positive control rats received a compound-free diet, while the negative control group consisted of untreated young animals. The cyto-protective effects of -lipoic acid and superoxide dismutase were investigated by morphological analysis of retinal and optic nerve head sections. The level of nuclear DNA damage was assessed by TUNEL fluorescent reaction. Lipo-peroxidation assays evaluated the oxidative stress and consequent alteration of the cell membrane function. Apoptotic phenomena were investigated by immuno-localization and Western blotting to measure the expression of caspase-3 and inducible nitric oxide synthase. The results reported in this work provide evidence that-lipoic acid and superoxide dismutase counteract the degenerative damage in aging animals, reducing the effects of oxidative stress.

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Damage to Rat Retinal DNA Induced In Vivo by Visible Light

Cited by 10 publications

References 14 publications

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

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

Continuing Damage to Rat Retinal DNA During Darkness Following Light Exposure

Neurodegenerative and Morpho-functional Alterations During Senescence: Positive Modulation by Lipoic Acid and Superoxide Dismutase Ocular Senescence in a Rat Model

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