Previous studies have shown that short-wavelength blue visible light induces retinal injury and may be a risk factor for age related macular degeneration. A2E is a blue light absorbing retinal chromophore that accumulates with age. Our previous in vitro studies have determined that, although A2E itself has a low phototoxic efficiency, the oxidation products of A2E that are formed in the presence of visible light can contribute to observed retinal pigment epithelial photodamage. The purpose of this study was to investigate the effects of blue light on retinal phototoxicity and its relationship to A2E, oxidized A2E and its isomers. Sprague-Dawley albino rats were dark adapted for 24 h. Control rats remained in the dark while experimental rats were exposed to blue light (λ = 450 nm, 3.1 mW cm(-2)) for 6 h. Isolated retinas were homogenized in Folch extraction mixture and then in chloroform. The dried extracts were reconstituted and divided for determination of organic soluble compound. Esters of fatty acids were determined with GC-MS, A2E and other chromophores using HPLC, and A2E oxidation products with LC-MS. Exposure of rat eyes to blue light did not significantly change the fatty acid composition of the retina. The A2E concentration (normalized to fatty acid content) in blue light exposed animals was found to be lower than the A2E concentration in control rats. The concentrations of all-trans-retinal-ethanolamine adduct and iso-A2E a precursor and an isomer of A2E respectively, were also lower after blue-light exposure than in the retinas of rats housed in the dark. On the other hand, the amount of oxidized forms of A2E was higher in the animals exposed to blue light. We conclude that in the rat eye, blue-light exposure promotes oxidation of A2E and iso-A2E to the products that are toxic to retinal tissue. Although high concentrations of A2E may be cytotoxic to the retina, the phototoxicity associated with blue light damage to the retina is in part a result of the formation of toxic A2E oxides. This effect may partially explain the association between blue light induced retinal injury and macular degeneration.
"We have previously shown that retinal irradiation with 670-nm light attenuates photoreceptor apoptosis induced by exposure to bright continuous white light (BCL) in rats
, a model with pathogenic features in common with the atrophic ‘dry’ form of AMD
[45-49]. Additionally, we have shown that a suite of complement-related genes are upregulated following BCL exposure, and that C3 is expressed in the retina by infiltrating monocytes/microglia
[Show abstract][Hide abstract] ABSTRACT: Aim
Complement activation is associated with the pathogenesis of age-related macular degeneration (AMD). We aimed to investigate whether 670-nm light treatment reduces the propagation of complement in a light-induced model of atrophic AMD.
Sprague–Dawley (SD) rats were pretreated with 9 J/cm2 670-nm light for 3 minutes daily over 5 days; other animals were sham treated. Animals were exposed to white light (1,000 lux) for 24 h, after which animals were kept in dim light (5 lux) for 7 days. Expression of complement genes was assessed by quantitative polymerase chain reaction (qPCR), and immunohistochemistry. Counts were made of C3-expressing monocytes/microglia using in situ hybridization. Photoreceptor death was also assessed using outer nuclear layer (ONL) thickness measurements, and oxidative stress using immunohistochemistry for 4-hydroxynonenal (4-HNE).
Following light damage, retinas pretreated with 670-nm light had reduced immunoreactivity for the oxidative damage maker 4-HNE in the ONL and outer segments, compared to controls. In conjunction, there was significant reduction in retinal expression of complement genes C1s, C2, C3, C4b, C3aR1, and C5r1 following 670 nm treatment. In situ hybridization, coupled with immunoreactivity for the marker ionized calcium binding adaptor molecule 1 (IBA1), revealed that C3 is expressed by infiltrating microglia/monocytes in subretinal space following light damage, which were significantly reduced in number after 670 nm treatment. Additionally, immunohistochemistry for C3 revealed a decrease in C3 deposition in the ONL following 670 nm treatment.
Our data indicate that 670-nm light pretreatment reduces lipid peroxidation and complement propagation in the degenerating retina. These findings have relevance to the cellular events of complement activation underling the pathogenesis of AMD, and highlight the potential of 670-nm light as a non-invasive anti-inflammatory therapy.
Journal of Neuroinflammation 11/2012; 9(1):257. DOI:10.1186/1742-2094-9-257 · 5.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The key physiological functions of the rhodopsin molecule are reviewed. Molecular mechanisms of visual pigments spectral tuning, photoisomerization of the 11-cis-retinal chromophore that triggers the phototransduction process, formation of physiologically active state of rhodopsin as a G-protein-coupled receptor, rhodopsin visual cycle, and consequences of its impairment are evaluated. Visual pigment rhodopsin performs several functions, providing spectral sensitivity of photoreceptor cells, phototransduction processes and light and dark adaptation. Genetically determined defects of visual pigment molecule and proteins involved into mechanisms of phototransduction and adaptation or into mechanism of visual cycle are directly linked to pathogenesis of different forms of degenerative retina diseases. Understanding the molecular mechanisms of these physiological processes uncovers the way to direct investigation of pathogenesis of these severe eye diseases.
Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology 04/2012; 6(2). DOI:10.1134/S1990747812010084
[Show abstract][Hide abstract] ABSTRACT: To investigate the expression and localization of complement system mRNA and protein in a light-induced model of progressive retinal degeneration.
Sprague-Dawley (SD) rats were exposed to 1000 lux of bright continuous light (BCL) for up to 24 hours. At time points during (1-24 hours) and after (3 and 7 days) exposure, the animals were euthanatized and the retinas processed. Differential expression of complement genes at 24 hours of exposure was assessed using microarray analysis. Expression of complement genes was validated by quantitative PCR, and expression of selected genes was investigated during and after BCL exposure. Photoreceptor apoptosis was assessed using TUNEL and C3 was further investigated by spatiotemporal analysis using in situ hybridization and immunohistochemistry.
Exposure to 24 hours of BCL induced differential expression of a suite of complement system genes, including classic and lectin components, regulators, and receptors. C1qr1, MCP, Daf1, and C1qTNF6 all modulated in concert with photoreceptor death and AP-1 expression, which reached a peak at 24 hours exposure. C1s and C4a reached peak expression at 3 days after exposure, while expression of C3, C3ar1, and C5r1 were maximum at 7 days after exposure. C3 mRNA was detected in ED1- and IBA1-positive microglia/macrophages, in the retinal vessels and optic nerve head and in the subretinal space, particularly at the margins of the emerging lesion.
The data indicate that BCL induces the prolonged expression of a range of complement genes and show that microglia/macrophages synthesize C3 and deposit it in the ONL after BCL injury. These findings have relevance to the role of complement in progressive retinal degeneration, including atrophic AMD.
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