Abstract
Purpose: :
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.
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: photoreceptors • retinal degenerations: hereditary • apoptosis/cell death