Steroids Do Not Prevent Photoreceptor Degeneration in the Light-Exposed T4R Rhodopsin Mutant Dog Retina Irrespective of AP-1 Inhibition

The differentiated photoreceptor is elegantly organized to have an external light-capturing outer segment optimized for efficient quantal absorption. Internally, the inner segment has the protein synthetic and energy-generating organelles, and on the vitreal aspect is the synaptic terminal that connects to the second-order neurons that ultimately transfer information to higher visual centers. Each rod photoreceptor can be 120 μm or longer, and such exquisite compartmentalization efficiently separates multiple specialized functions. Not surprisingly, the photoreceptors' complexity, together with the specific signal transduction and “housekeeping” functions performed, renders them susceptible to degenerative diseases, either genetic or acquired, that result from damage to genes or pathways critical for their function or viability. Of the 190 retinal disease loci mapped to date, the genes and mutations have been identified for ∼135 (RetNet available at http://www.sph.uth.tmc.edu/RetNet/ provided in the public domain by the University of Texas Health Science Center, Houston, TX). In many cases, different mutations in the same gene result in a broad range of differing phenotypes, thus emphasizing the broad genetic and allelic heterogeneity of these degenerative retinal disorders. Of particular interest has been the interaction between light and the death of photoreceptors. After Noell et al.1,2 made the seminal finding that visible light may damage mammalian photoreceptors at intensities that are ordinarily encountered, many investigators in subsequent studies have examined this interaction, especially in normal albino rodents, and have begun to identify the pathways and molecular events that link exposure to light to photoreceptor degeneration.3,4 Two different pathways, the bright- and low-light pathways, mediate light-induced visual cell death, but only the bright-light pathway is accompanied by activation of the AP-1 transcription factor.5 This critical intermediary has been proposed to link damaging exposure to lights with photoreceptor apoptosis by activation of the c-Fos/AP-1 molecular pathway.5 Photoreceptor degeneration also results from exposure to light in retinas having mutations in the rhodopsin gene (RHO) that renders them especially sensitive to light. The naturally occurring T4R6 and transgenic T17M7 RHO mutations in dogs and mice, respectively, represent models for homologous diseases in humans with autosomal dominant retinitis pigmentosa (adRP).8,9 Although these mutations affect the first- and second-consensus glycosylation sequences,10 a possible indication of the enhanced light-damage susceptibility, other RHO mutations in humans also show marked delays in visual pigment regeneration with bleaching,11-13 a feature that raises concern as to the possible modulatory effect that exposure to light can have on the disease process.6,14 Although light-induced damage in both normal mice, and RHO mutant dogs or mice is mediated by RHO, the major difference between normal and mutant subjects is that, in the latter, photoreceptors degenerate with light intensities that cause no damage to normal retinas. Very short exposures to light, such as those used in routine clinical eye examinations of humans, result in severe outer retinal degeneration.14,15 Previous studies in albino rodents using genetic or pharmacologic approaches have demonstrated an association between AP-1 inhibition and prevention of photoreceptor degeneration.16-18 Although there are some questions as to the specificity of this inhibition and the role of AP-1 as a cell death or cell survival signal,19 it is clear that high-dose administration of corticosteroids before exposure to light is associated with no photoreceptor degeneration.18 In this study, we examined the effect of systemic or ocular corticosteroid administration on AP-1 induction and photoreceptor degeneration. We found that only systemic steroids inhibit AP-1 activation, but in neither case do steroids prevent or modulate photoreceptor damage. This supports prior findings that, at least in the T4R RHO mutant canine retina, AP-1 is not the critical player in the cell death signaling pathway that links exposure to light and photoreceptor degeneration.19