The Potential of Ambient Light Restriction to Restore Function to the Degenerating P23H-3 Rat Retina

ArticleinAdvances in Experimental Medicine and Biology 613:193-9 · February 2008with3 Reads
Impact Factor: 1.96 · DOI: 10.1007/978-0-387-74904-4_22 · Source: PubMed

Reviewing, in 1999, the non-genetic factors that regulate retinal degeneration, we (Stone et al., 1999) hypothesized that the loss of vision during degeneration results only partly from photoreceptor death. Significant visual loss results, we argued, from loss of performance in surviving photoreceptors, and might be reversible. To test the idea, we first demonstrated that, in the rhodopsin-mutant P23H-3 transgenic rat, the retina is hypersensitive to modest levels of ambient light, which accelerate photoreceptor death, shorten outer segments and degrade the ERG more severely than in non-degenerative controls (Walsh et al., 2004). A comparable hypersensitivity to ambient light has since been reported in a rhodopsin-mutant degeneration which occurs naturally in the dog (Cideciyan et al., 2005).

    • "Retinal dystrophies are a diverse group of conditions with the common feature of photoreceptor degeneration. Many have a genetic basis [1] but environmental factors, such as oxygen [2] and ambient light [3–6], play a role in determining their phenotype. This study concerns the impact of excess oxygen on nondegenerative photoreceptors in the C57BL/6 mouse. "
    [Show abstract] [Hide abstract] ABSTRACT: Hyperoxia is specifically toxic to photoreceptors, and this toxicity may be important in the progress of retinal dystrophies. This study examines gene expression induced in the C57BL/6J mouse retina by hyperoxia over the 14-day period during which photoreceptors first resist, then succumb to, hyperoxia. Young adult C57BL/6J mice were exposed to hyperoxia (75% oxygen) for up to 14 days. On day 0 (control), day 3, day 7, and day 14, retinal RNA was extracted and processed on Affymetrix GeneChip Mouse Genome 430 2.0 arrays. Microarray data were analyzed using GCOS Version 1.4 and GeneSpring Version 7.3.1. For 15 genes, microarray data were confirmed using relative quantitative real-time reverse transcription polymerase chain reaction techniques. The overall numbers of hyperoxia-regulated genes increased monotonically with exposure. Within that increase, however, a distinctive temporal pattern was apparent. At 3 days exposure, there was prominent upregulation of genes associated with neuroprotection. By day 14, these early-responsive genes were downregulated, and genes related to cell death were strongly expressed. At day 7, the regulation of these genes was mixed, indicating a possible "transition period" from stability at day 3 to degeneration at day 14. When functional groupings of genes were analyzed separately, there was significant regulation in genes responsive to stress, genes known to cause human photoreceptor dystrophies and genes associated with apoptosis. Microarray analysis of the response of the retina to prolonged hyperoxia demonstrated a temporal pattern involving early neuroprotection and later cell death, and provided insight into the mechanisms involved in the two phases of response. As hyperoxia is a consistent feature of the late stages of photoreceptor degenerations, understanding the mechanisms of oxygen toxicity may be important therapeutically.
    Full-text · Article · Feb 2008 · Molecular vision
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  • [Show abstract] [Hide abstract] ABSTRACT: To follow the status of cones over the life of the P23H-3 transgenic rat, while the rod population is depleted. P23H-3 heterozygous and Sprague-Dawley (SD) control rats were raised in dim, cyclic light from postnatal day (P)10 to P540. Retinas were examined for cone density, cone outer segment (OS) length, cone axon and soma morphology, and the amplitude of rod and cone components of the electroretinogram (ERG) were determined. In the P23H-3 retina, cone density followed a developmental pattern, increasing from P10 until P20, declining during early adult life (to P150), then steadying at levels found in the SD retina until P540. Cone OSs elongated to P30 and then slowly shortened during late adulthood; at P350 and P540, cone OSs were significantly shorter than in the background SD strain. Cone axons shortened slowly throughout adult life as the outer nuclear layer thinned. The rod a-wave declined steadily in the P23H-3 retina from P10, falling below amplitudes seen in the SD strain from early life. By contrast, the cone b-wave maintained amplitude at SD levels, until P380. Despite the ongoing loss of rod function and numbers, cone numbers in the P23H-3 retina were maintained at levels found in the SD rat to the oldest age examined, and cone function and OS morphology were maintained for approximately 1 year, indicating a long period of cone independence. The long period of cone survival creates an opportunity to induce self-repair, if the stress causing their dysfunction can be reduced.
    No preview · Article · May 2009 · Investigative ophthalmology & visual science
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  • [Show abstract] [Hide abstract] ABSTRACT: This study evaluated the capacity of Xenopus laevis retina to regenerate photoreceptor cells after cyclic light-mediated acute rod photoreceptor degeneration in a transgenic P23H mutant rhodopsin model of retinits pigmentosa. After discontinuation of cyclic light exposure, we monitored histologic progression of retinal regeneration over a 3 week recovery period. To assess their metabolomic states, contralateral eyes were processed for computational molecular phenotyping. We found that retinal degeneration in the P23H rhodopsin mutation could be partially reversed, with regeneration of rod photoreceptors recovering normal morphology (including full-length rod outer segments) by the end of the 3 week recovery period. In contrast, retinal degeneration mediated by directly induced apoptosis did not recover in the 3 week recovery period. Dystrophic rod photoreceptors with truncated rod outer segments were identified as the likely source of rod photoreceptor regeneration in the P23H retinas. These dystrophic photoreceptors remain metabolically active despite having lost most of their outer segments.
    No preview · Article · Feb 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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