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I. R. Rodriguez, S. J. Fliesler; Photo-Damage Generates 7-Keto- and 7-Hydroxycholesterol in the Rat Retina via a Free Radical-Mediated Mechanism. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5188.
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Albino rats undergo photoreceptor degeneration after exposure to intense constant light. However, the molecular mechanism(s) underlying such degeneration is not fully understood. The purpose of this study was to determine if such conditions can cause the formation of toxic oxysterols in the retina.
Adult Sprague-Dawley rats were subjected to photo-damage for 24 h as previously described (Organisciak et al., IOVS 37: 2243-57, 1996). Lipid extracts from photo-damaged and unexposed control retinas were analyzed for oxysterols by LCMS. Immunohistochemistry (using commercially available antibodies) was used to determine the localization of 7-ketocholesterol (7kCh) before and after photo-damage. The ability of ferritin to catalyze formation of cholesterol oxidation products in LDL particles, with or without light exposure, also was examined.
Photo-damaging conditions caused marked elevation of two known cytotoxic oxysterols, 7kCh and 7-hydroxycholesterol (7HCh) in the retinas. 7-Ketocholesterol and 7HCh levels were 6-fold and 50-fold higher, respectively, than in controls. More importantly, two key intermediates (5,6-epoxycholesterol and 7-hydroperoxy-cholesterol) were also identified, indicating that a free radical-mediated mechanism was involved in the oxysterol formation. Immunohistochemistry localized 7kCh to the ganglion cell layer, photoreceptor inner segments, and RPE, coinciding with ferritin localization. In the presence of light, ferritin promoted marked oxidation of LDL particles, resulting in 7kCh and 7HCh formation.
Photo-damage increases the levels of two known cytotoxic oxysterols in the retina. The cytological distribution of 7kCh in the photo-damaged retina also coincides with that of ferritin. The ability of ferritin to oxidize lipids in LDL in the presence of light suggests a possible source for iron as a free radical catalyst. The increased levels of 7kCh in photoreceptor inner segments suggests it may be responsible for the photoreceptor degeneration observed in these photo-damaged rats.
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