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G. D. Aguirre, D. Gu, S. Pearce-Kelling, Z. Li, G. M. Acland, W. A. Beltran; Systemic but Not Intravitreal Steroids Inhibit AP-1 in Light Exposed T4R Rhodopsin Mutant Dog Retina, but Neither Prevent Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4412.
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AP-1 has been proposed as the key intermediate linking light exposure and photoreceptor cell death in rodent light damage models as steroid administration, which prevents light damage, is associated with AP-1 inhibition. Unlike the case in normal rodents, we have suggested that AP-1 is a cell survival rather than a cell death signal in the T4R RHO mutant dog retina (Gu et al., 2007). We now examine the role of steroids in inhibiting AP-1 activation and/or in preventing photoreceptor degeneration.
T4R RHO mutant dogs were dark adapted overnight. Both eyes were dilated with mydriatics; the fundus of the left eye was photographed (~15-17 overlapping frames) using a Kowa RC-2 fundus camera, while the right eye was patched and unexposed to light. Dogs remained in the dark for 1-3 hrs after exposure for biochemical studies. 24 hrs prior to light exposure, some dogs were treated with systemic dexamethasone (DEX) or intravitreal/subconjunctival triamcinolone (TRIAM). AP-1 DNA binding activity was determined by EMSA, and phosphorylation of c-Fos and activation of ERK1/2 by immunoblotting; eyes were collected at 2 and 4 weeks after light exposure for histopathology.
Inhibition of AP-1 activation, and ERK1/2 and of c-Fos phosphorylation were found following systemic DEX treatment in light exposed T4R RHO mutant dog retinas. In contrast, AP-1 activation, phosphorylation of c-Fos and activation of ERK1/2 were not inhibited following light exposure in TRIAM-treated mutant retinas. In either case, however, extensive photoreceptor degeneration was found after light exposure.
Intraocular or systemic steroids fail to prevent light induced photoreceptor degeneration in the T4R RHO mutant dog retina. Finding that systemic DEX prevents AP-1 activation, yet has no effect in preventing retinal light damage, further supports the hypothesis that, at least in the RHO mutant canine retina, AP-1 is not the cell-death signal.
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