Abstract
It is well known that age-related macular degeneration (AMD) is an irreversible neurodegenerative disease that can cause blindness in the elderly. Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is a part of the pathogenesis of AMD. In this study, we evaluated the protective effect and mechanisms of alpha-mangostin (α-mangostin, α-MG) against NaIO3-induced reactive oxygen species (ROS)-dependent toxicity, which activates apoptosis in vivo and in vitro. MTT assay and flow cytometry demonstrated that the pretreatment of ARPE-19 cells with α-MG (0, 3.75, 7.5, and 15 μM) significantly increased cell viability and reduced apoptosis from NaIO3-induced oxidative stress in a concentration-dependent manner, which was achieved by the inhibition of Bax, cleaved PARP-1, cleaved caspase-3 protein expression, and enhancement of Bcl-2 protein. Furthermore, pre-incubation of ARPE-19 cells with α-MG markedly inhibited the intracellular ROS and extracellular H2O2 generation via blocking of the abnormal enzyme activities of superoxide dismutase (SOD), the downregulated levels of catalase (CAT), and the endogenous antioxidant, glutathione (GSH), which were regulated by decreasing PI3K-AKT-PGC-1α-STRT-3 signaling in ARPE-19 cells. In addition, our in vivo results indicated that α-MG improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer by inhibiting the expression of cleaved caspase-3 protein. Taken together, our results suggest that α-MG effectively protects human ARPE-19 cells from NaIO3-induced oxidative damage via antiapoptotic and antioxidant effects.
Highlights
Retinal pigmented epithelial cells (RPEs) are located between photoreceptor cells and Bruch’s membrane [1]
The results suggested that the expression of PI3K and phosphorylation of AKT on ARPE-19 cells were significantly increased after 24 h of NaIO3 treatment compared with the normal control group, which had been downregulated by α-MG (Figure 7A,B)
Along with the result of α-MG on the depression of PGC-1α and SIRT-3 protein levels, we found that α-MG protected RPE cells against NaIO3 -induced oxidative damage by reducing the SIRT-3 expression mediated by the PI3K/AKT/ PGC-1α signaling pathway
Summary
Retinal pigmented epithelial cells (RPEs) are located between photoreceptor cells (cone and rod cells) and Bruch’s membrane [1]. Abnormal RPEs are regarded as playing an important role in agerelated macular degeneration (AMD), a disease that results in irreversible center vision loss in the elderly population. This disease can generally be divided into two categories: dry AMD and wet AMD. The former is characterized by accumulation of drusen in the retina, thickening of Bruch’s membrane, RPE cell and photoreceptor dysfunction, and severe abnormal neovascularization (angiogenesis), which grows into the central region of the retina, leading to retinal exudation, hemorrhage, and, eventually, serious impairment of vision [3,4]. There are currently no effective treatment options for dry AMD
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