Retinal degeneration and local oxygen metabolism

Yu, Dao‐Yi; Cringle, Stephen J.

doi:10.1016/j.exer.2005.01.018

Cited by 298 publications

(229 citation statements)

References 16 publications

Supporting

Mentioning

222

Contrasting

Unclassified

Order By: Relevance

“…The ongoing visual processes require large amounts of energy, which cause the retina to have the highest oxygen consumption in the mammalian brain. 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.…”

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

View full text Add to dashboard Cite

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;

show abstract

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

View full text Add to dashboard Cite

show abstract

“…7DHC is well-known to be extremely prone to autooxidation (far more so than is cholesterol), particularly when exposed to light, generating oxysterol products that are extremely cytotoxic (Girotti, 2002). The retina (particularly the photoreceptor cells) is exposed to a high flux of oxygen (Cringle et al, 1991(Cringle et al, , 2002Yu and Cringle, 2005). Hence, it is reasonable to suspect that the in situ formation of 7DHC in a highly oxidizing environment would result in the progressive conversion of at least some of the 7DHC to oxysterols, which would then compromise cellular functions and viability, ultimately resulting in the observed retinal degeneration.…”

Section: Discussionmentioning

confidence: 99%

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

Vaughan

Peachey

Richards

et al. 2006

Experimental Eye Research

View full text Add to dashboard Cite

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.

show abstract

“…1985). Vessel attenuation is thought predominantly to reflect the reduced metabolic demand of the degenerated retina, where loss of oxygen consumption leads to an increase in local oxygen levels in the retina, ultimately resulting in vasoconstriction (Yu & Cringle 2005; Ma et al. 2012).…”

Section: Introductionmentioning

confidence: 99%

Optical coherence tomography angiography in patients with retinitis pigmentosa who have normal visual acuity

Takagi

Hirami

Takahashi

et al. 2018

Acta Ophthalmologica

View full text Add to dashboard Cite

PurposeTo investigate flow area changes measured using optical coherence tomography angiography (OCTA; RTVue XR Avanti®) in patients with retinitis pigmentosa (RP) with preserved visual acuity (VA).MethodsThis was an age‐ and refraction‐matched case–control study. Consecutive patients with a best‐corrected visual acuity (BCVA) of ≥20/20 and normal subjects were recruited. Fifty eyes (32 patients) and 22 eyes (12 controls) were included. The flow area and foveal avascular zone (FAZ) were measured in both superficial and deep layers within a 3 × 3 mm central area of the fovea. Association between OCTA parameters and the length of the inner segment ellipsoid (ISe) and external limiting membrane (ELM), the area without abnormal fluorescence in fundus autofluorescence (normal FAF area ratio) and the area of I‐2e of the Goldmann perimeter were analysed using mixed‐effects regression analysis.ResultsFoveal avascular zones were significantly smaller in patients with RP than in controls in superficial (p = 0.004) but not in deep layers (p = 0.25). The flow area in superficial (p = 0.007) and deep layers (p = 0.004) was significantly smaller in patients with RP than in controls. In patients with RP, flow areas in the superficial layers, but not in the deep layers, were significantly associated with the lengths of ISe (p = 0.001) and ELM (p = 0.002) and the I‐2e area (p = 0.036), but not with the normal FAF area ratio (p = 0.399).ConclusionOptical coherence tomography angiography (OCTA)‐measured flow area in superficial layers gradually reduced with RP progression and may be a useful parameter of RP pathogenesis.

show abstract

Retinal degeneration and local oxygen metabolism

Cited by 298 publications

References 16 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

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

Optical coherence tomography angiography in patients with retinitis pigmentosa who have normal visual acuity

Contact Info

Product

Resources

About