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Albarracin et al. BMC Neuroscience 2013, 14:125 http://www.biomedcentral.com/1471-2202/14/125 upregulation occurs in conjunction with high levels of ex- pression of the oxidative stress markers, and increased rate of cell death (Figure 5). However, in the treated retinas there was a much smaller rise in C3 expression (5- fold in 10dTr retinas, Figure 10B). This finding is consist- ent with reports from studies carried out in aged rodents [48] and in rats exposed to damaging bright light [15,17]. Dysregulation of C3 plays a highly significant role in ret- inal diseases, and dysregulation of complement is highly associated with risk of AMD [49,50,52]. Several lines of evidence suggest that oxidative stress triggers complement activation [53,54], which in turn mediates local inflamma- tion. Tissue damage may result from cell-mediated attack, or by the formation of membrane attack complex, which kills cells. The low levels of C3 expression in the treated retinas in this study, suggest that 670 nm light is a poten- tial therapeutic tool applicable to retinal degenerative con- ditions where inflammation is involved, such as AMD. 670 nm light treatment reduces retinal damage Several studies of retinal degeneration report an increase in expression of neuroprotective factors such as Fgf-2 over time, which protects the retina by delaying, or in some cases, reducing photoreceptor cell death [51,55-57]. It has been reported previously that exposing the retina to a hyperoxic environment induces changes in the expression of Fgf-2 [29,55]. The current study also demonstrates that Fgf-2 expression is modulated by 670 nm light in hyper- oxic conditions, although the effect is complex. In this model, cell death in the ONL increases over time spent in hyperoxia, and at the 7d timepoint there are high levels of cell death in the NT group, and only low levels of cell death in the Tr group (Figures 5 and 6). Consistent with a role in neuroprotection, Fgf-2 expression is higher in the 7dTr group (low levels of cell death) compared with the 7dNT group (Figure 10C). However, Fgf-2 expression is significantly lower in 10dTr animals (compared with 10dNT) which is consistent with a finding that by 10d ex- posure to hyperoxia there are high levels of cell death, even in the retinas of treated animals. Beyond this timepoint Fgf-2 expression remains approximately static. The explanation for the lowering of levels of Fgf-2 in 10dTr and 14dTr is not immediately apparent, but may reflect the limitations of the efficacy of 670 nm light in offsetting the effects of hyperoxia. However, the reasons why 670 nm light treatment reaches a plateau, or declines, at this stage cannot be explained until we have a better understanding of its mechanism of action. 670 nm light in hyperoxia-induced retinal degeneration The present findings indicate that the mechanism of ac- tion of 670 nm light is likely to involve signalling path- ways activated by oxidative stress in the retina. It is generally accepted that oxidative stress initiates and Page 10 of 14 facilitates the progression of hyperoxia-induced damage in the central nervous system and in the retina [31,58]. High oxygen tension is believed to induce metabolic dis- turbances in the PUFA-rich photoreceptor outer seg- ments that trigger formation of ROS [35]. Accumulation of ROS leads to oxidative stress, and in turn to inflam- mation, and ultimately loss of functional vision [59,60]. Exposure of the retina to 670 nm light has been sug- gested to initiate key signalling pathways that activate transcription factors [61] to modulate pro/anti-oxidant balance in tissues [46], inflammatory responses [16,17] and cytoprotection [12-15]. The present results support those findings in that the data indicates that 670 nm light treatment limits oxidative stress and proinflammation, re- ducing retinal stress and cell death. Several reports have suggested the important role of mitochondria in mediating the effects of 670 nm light ir- radiation [18,28]. First, the mitochondrial cytochrome oxi- dase has been proposed as the endogenous primary photoacceptor molecule in the reception of 670 nm light triggering secondary cellular processes such as enhanced energy-rich adenosine triphosphate (ATP) synthesis and other various modulatory effects [18,20]. Second, 670 nm light was suggested to influence retrograde signalling be- tween the mitochondria and the nucleus, resulting in enhanced synthesis of DNA and RNA [28]. Third, the intra-mitochrondrial activities of nitric oxide (NO) and the cytochrome oxidase have recently been proposed as a novel mechanism of action of 670 nm light [62,63]. NO controls oxygen consumption of the tissue through re- versible and competitive binding to cytochrome oxidase [64]. In a recent review, Poyton and Ball provided a mech- anistic explanation suggesting that 670 nm light may cause dissociation of NO from the cytochrome oxidase complex allowing NO to bind effectively to oxygen during tissue damage [65]. Conclusion Here, we have demonstrated that hyperoxia-induced oxi- dative stress, cell death, retinal stress and inflammation were significantly mitigated, but not abolished, by 670 nm light treatment. Oxygen toxicity has been shown to cause oxidative stress and inflammation triggering photoreceptor cell death which are also implicated in the late stages of retinal degenerative conditions in humans, such as AMD, RP and Retinopathy of Prema- turity (ROP) [66-68]. Hence, 670 nm red light treatment has the potential to slow the progression of retinopathies and conditions involving oxidative stress. Methods Animals All procedures were in accordance with the Association for Research in Vision and Ophthalmology (ARVO) StatementPDF Image | 670 nm light mitigates oxygen-induced degeneration 2013
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