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Albarracin et al. BMC Neuroscience 2013, 14:125 http://www.biomedcentral.com/1471-2202/14/125 unproven, this process is also thought to stimulate signal- ling pathways resulting in improved mitochondrial energy metabolism, antioxidant production, cell survival and regulation of non-coding RNAs [17,20]. Prolonged exposure to an elevated concentration of oxy- gen (hyperoxia) is toxic to a number of tissues in the respiratory and central nervous systems [21,22]. In the ret- ina, early investigations in neonatal and adult rabbits and in adult mice demonstrated that exposure to hyperoxia can cause severe damage to photoreceptors [23-25]. The most commonly-observed pathological effects in the hyperoxia- induced mouse model are photoreceptor and endothelial cell death, increased inflammation, oxidative stress, erosion of the blood-retina barrier (BRB) and loss of functional vision [26,27,29-31]. These changes are site-specific, such that the irreversible loss of photoreceptors is most promin- ent in the circumscribed area of the inferior retina, ap- proximately 500 μm from the optic disk [32]. Although the precise mechanism for the photoreceptor vulnerability to hyperoxia is not completely understood, it is postulated to be initiated and sustained by a “toxic cycle” of events [26], involving hyperoxia-induced oxida- tive stress in the outer retina through generation of free radicals and reactive oxygen species (ROS). Given the in- effective or lack of autoregulatory mechanism for the oxy- gen supply in the outer retina [33], prolonged exposure to hyperoxia will inevitably cause an increase in ROS pro- duction by the photoreceptors. Generation of ROS will subsequently trigger various pathological changes, such as oxidative damage, particularly in photoreceptors. These light sensitive cells contain a large number of polyunsatur- ated fatty acid (PUFA), that are also highly sensitive to ROS [34]. The hyperoxia-induced depletion of photore- ceptors can also contribute to the rise of oxygen tension, ROS accumulation which in turn leads to further cell death, and progression of degeneration. These changes are also featured in the later stages of Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP) [35,36], suggesting that hyperoxia may be a suitable model for investigating novel rescue strategies to slow down the progression of these diseases. Page 2 of 14 thickness following 3d and 7d exposure to hyperoxia. However, a significant reduction in ONL thickness was observed in the inferior central retina at 10d and 14d ex- posure (p < 0.001). In the inferior peripheral retina, a small (not significant) reduction in ONL thickness was detected at 10d followed by a significant thinning at this location at 14d exposure (p < 0.05). Secondly, to further explore the regional effects of photoreceptor loss, we measured the ONL thickness and photoreceptor nuclei density at 1 mm intervals along the vertical meridian of the retina in both groups, nontreated (NT) and treated (Tr), at all timepoints. These data are summarized in Figures 2 and 3. The results showed no sig- nificant difference in retinal thickness and photoreceptor nuclei density in the NT and Tr groups at 0d (Figure 2A; solid black vs broken black lines and Figure 3A-B). Follow- ing 3d exposure to hyperoxia (Figure 2A; solid red vs broken red lines), there was also no change in the ONL thickness between NT and Tr groups. At 7d, treated ani- mals (Figure 2A; solid blue line) showed a thicker ONL, but the difference between these and the 7dNT animals (Figure 2A; broken blue line) is not statistically significant (n = 12). After 10d exposure, the ONL is thinner in the in- ferior retina in both groups (10dNT and 10dTr) but indi- cates no significant difference between these groups (Figure 2A; solid purple vs broken purple lines). However, after 14d exposure to hyperoxia the ONL in the inferior retina is significantly thicker in 14dTr (Figure 2B-C, broken green line, Figure 3A) animals compared to 14dNT (Figure 2B-C, solid green line and Figure 3A) (p < 0.001). There is no significant difference in ONL thickness in superior region of the retina (central and periphery) in these groups (Figure 2B). Furthermore, the photo- receptor nuclei density counts in the inferior central area (Figure 3B) revealed a 60% decline in nontreated retinas (black bar) following 14d of hyperoxia exposure; while the 670 nm-treated groups (red bar) only showed a reduction of 15% compared with control baseline. The difference between 14dNT and 14dTr groups is statisti- cally significant (p < 0.01). TUNEL (cell death) analysis Findings from the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay analysis are shown in Figures 4, 5, and 6. There was virtually no TUNEL + labelling detected in control retinas from 0dNT and 0dTr groups (Figure 4). In the 3dNT group there was a photo- receptor-cell specific death (Figure 4, red dots) confined almost exclusively to a circumscribed area approximately 500 μm inferior to the optic nerve head (the ‘hotspot’) (Figure 5A, solid red line) consistent with a previous report [30]; in 3dTr animals, only a small increase in TUNEL + cells was detected above baseline in the hotspot area (Figure 4, red dots and Figure 5A, red broken line). After In this study we aimed to treatment with 670 nm light apoptosis and inflammatory induced retinopathy in adult Results Photoreceptor survival examine the effects of pre- on levels of oxidative stress, response in the hyperoxia- mouse retina. Firstly, we evaluated the time course of the effects of hyperoxia on photoreceptor survival across the retina (Figure 1A). As depicted in Figure 1B, there was no sig- nificant change in outer nuclear layer (ONL) thickness in the superior retina at any of the timepoints. In the in- ferior retina, there was no significant change in ONLPDF Image | 670 nm light mitigates oxygen-induced degeneration 2013
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