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Shimon Ben-Shabat, Orit Adir, Elie Beit-Yannai, Zeev Dvashi, Ayala Pollack; Potential protective role of the CB2 cannabinoid receptor system in the crosstalk between autophagy and cellular senescence of RPE cells. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5017.
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© ARVO (1962-2015); The Authors (2016-present)
Accumulation in the Retinal Pigment Epithelial (RPE) cells of A2E, a pyridinium bis-retinoid, has the potential to cause RPE cell death and may contribute to the RPE cell atrophy observed in AMD. The cannabinoid receptor system is present in human RPE cells and is intimately involved in the oxidative damage process, including that associated with AMD. It has been shown that levels of endocannabinoids are significantly increased in retinal tissue from AMD donors. This study aimed to investigate the crosstalk between autophagy and cellular senescence of RPE cells, on the in vitro AMD-A2E model in the presence and absence of cannabinoid (HU-308, a specific agonist of CB2).
By using A2E-loaded RPE cells we can mimic the oxidative stress taking place in AMD. The presence of autophagy and activation of the signalling pathway were assessed in the presence and absence of HU-308, a specific CB2 receptor agonist, by Western-blot analysis, flow-cytometry, ELISA and confocal microscope.
Following oxidative stress (100μM H2O2), A2E significantly (p<0.05) reduced LC3-I and LC3-II, Bcl-2, p65 and MAPKs activity, compared to cells treated with H2O2 alone. In contrast HU-308 significantly (p<0.05) increased LC3-I and LC3-II, p65 and MAPKs activity indicating proper activation of the autophagy process. Higher positive SA-β-Gal staining was found in A2E treated cells vs. control. This effect was significantly (p<0.05) increased when H2O2 was added, while HU-308 successfully blocked the increase in SA-β-Gal staining halting the process of cellular senescence in these RPE cells.
This research demonstrates that A2E alone might induce cellular senescence of RPE cells and have negative affect on these cells. Moreover, these results demonstrate that the CB2 cannabinoid receptor system may attenuate AMD generated by the accumulation of A2E. This study is expected to select candidate therapeutic compounds that may contribute to delaying or arresting A2E-related toxicity to the RPE cells.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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