Photoreceptors in the rat retina are specifically vulnerable to both hypoxia and hyperoxia

Abstract

The current study aims to assess the vulnerability of photoreceptors in rat retina to variations in tissue oxygen levels. Young adult Sprague-Dawley rats were exposed to air with the concentration of oxygen set at 10% (hypoxia), 21% (room air, normoxia), and four levels of hyperoxia (45%, 65%, 70%, and 75%), for up to 3 weeks. Their retinas were then examined for cell death, using the TUNEL technique. Hypoxia (10% oxygen) for 2 weeks caused a limited but significant rise in the frequency of TUNEL+ (dying) cells in the retina, the great majority (>90%) being located in the outer nuclear layer (ONL). Hyperoxia also induced an increase in the frequency of TUNEL+ cells, again predominantly in the ONL. The increase rose with duration of exposure, up to 2 weeks. At 2 weeks exposure, the increase was limited yet significant at 45% oxygen, and maximal at 65%. Where the frequencies of TUNEL+ cells were high, it was evident that photoreceptor death was maximal in the midperipheral retina. The adult retina is vulnerable to maintained shifts in oxygen availability to the retina, both below and above normal. The vulnerability is specific to photoreceptors; other retinal neurons appeared resistant to the exposures tested. Shifts in retinal oxygen levels caused by variations in ambient light, by the persistence of light through the normally dark (night) half of the day-night cycle, or by depletion of the photoreceptor population, may contribute to photoreceptor death in the normal retina.

Cone function in children with a history of preterm birth

“…Spatial cone density was investigated mostly in the foveal or parafoveal area, because in the periphery rods are known to be the dominant type of photoreceptors [20,21]. Cellular dysfunction is more probable; as high vulnerability of the developing foveal cones is previously described, and these are the immature photoreceptors which appear to be particularly vulnerable to retinal oxygen level fluctuation [22]. The results of the GEE statistics in our study are also in accordance with this second hypothesis.…”

NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

“…Using shRNA constructs to reduce either of these enzymes in photoreceptors led to an increase in oxidative damage and rapid cell death (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI79735DS1), demonstrating their importance in photoreceptor survival. Despite the hyperoxic environment and increased oxidative stress experienced by cones during rod degeneration in RP mice (29,(42)(43)(44), these antioxidant enzymes were not upregulated ( Figure 1, F-I). To provide a specific and long-term approach to enhance the antioxidative capacity of cones, it was possible that AAVs encoding such genes might prolong their survival.…”

Mathematical models of retinitis pigmentosa: The oxygen toxicity hypothesis

“…This corresponds to a timescale of decades for degeneration to spread across the retina (given that approximately 4000 photoreceptors lie along any direct path traced through the retina between the ora serrata and the fovea and assuming sequential cell death), a timescale consistent with degeneration in humans (Hartong et al, 2006). Further evidence supporting the role of hyperoxia in RP can be found in Cingolani et al (2006); Wellard et al (2005); Yamada et al (1999); for reviews, see Roberts (2015); Stone et al (1999); Cringle (2001, 2005).…”