Abstract
Slow, progressive rod degeneration followed by cone death leading to blindness is the pathological signature of all forms of human retinitis pigmentosa (RP). Therapeutic schemes based on intraocular delivery of neuroprotective agents prolong the lifetime of photoreceptors and have reached the stage of clinical trial. The success of these approaches depends upon optimization of chronic supply and appropriate combination of factors. Environmental enrichment (EE), a novel neuroprotective strategy based on enhanced motor, sensory and social stimulation, has already been shown to exert beneficial effects in animal models of various disorders of the CNS, including Alzheimer and Huntington disease. Here we report the results of prolonged exposure of rd10 mice, a mutant strain undergoing progressive photoreceptor degeneration mimicking human RP, to such an enriched environment from birth. By means of microscopy of retinal tissue, electrophysiological recordings, visual behaviour assessment and molecular analysis, we show that EE considerably preserves retinal morphology and physiology as well as visual perception over time in rd10 mutant mice. We find that protective effects of EE are accompanied by increased expression of retinal mRNAs for CNTF and mTOR, both factors known as instrumental to photoreceptor survival. Compared to other rescue approaches used in similar animal models, EE is highly effective, minimally invasive and results into a long-lasting retinal protection. These results open novel perspectives of research pointing to environmental strategies as useful tools to extend photoreceptor survival.
Highlights
Retinitis pigmentosa (RP) comprises a group of inherited retinal disorders with an incidence in humans of approximately 1/3500 [1,2]
In rd10 mice, rod loss starts around post-natal day 18 (P18), peaks at P24 and is almost complete by P40 [32]
Even in the central retina, where degeneration was faster, a continuous row of photoreceptors was observed in preparations from EE rd10 mice, while these cells appeared intermittent in the outer nuclear layer of retinas from standard laboratory conditions (ST) controls (Figure 2, C and D; Figure 3, C and D)
Summary
Retinitis pigmentosa (RP) comprises a group of inherited retinal disorders with an incidence in humans of approximately 1/3500 [1,2]. Cones, responsible for high-acuity daytime vision die, leading to blindness. A promising treatment is based upon neuroprotection, which aims to delay the intrinsically slow degenerative process of RP by interfering with the death of rods, given the finding that increased rod survival extends cone viability as well [6]. Because of the importance that cones have for everyday life, and considering that as little as 10% of the total cone number is sufficient for independent living in humans [1], developing treatments finalized to extend the lifespan of these cells are important. Clinical trials are currently testing the efficacy of intraocular devices releasing ciliary neurotrophic factor, CNTF [7,8,9]. The optimal combinations of neurotrophic factors to be delivered are to be defined [10,11] and the best dosages must be found to maintain appropriate regulation of neurotrophin levels avoiding adverse effects [12]
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