Abstract
Background: The purpose of this study is to investigate the antiangiogenic effect of Sanguinarine chloride (SC) on models of age-related macular degeneration (AMD) both in vivo and in vitro. Methods: Choroidal neovascularization (CNV) was conducted by laser photocoagulation in C57BL6/J mice. SC (2.5 μM, 2 μl/eye) was intravitreally injected immediately after laser injury. The control group received an equal amount of PBS. 7 days after laser injury, CNV severity was evaluated using fundus fluorescein angiography, hematoxylin and eosin (H&E) staining, and choroid flat-mount staining. Vascular endothelial growth factor (VEGF) expression in the retina/choroid complex was measured by western blot analysis and ELISA kit. In vitro, human retinal microvascular endothelial cells (HRMECs) were used to investigate the effects of SC on cell tube formation, migration, and cytotoxicity. The expression of VEGF-induced expression of extracellular signal-regulated kinase (ERK)1/2, protein kinase B (AKT), mitogen-activated protein kinases (p38-MAPK) in vitro and laser induced VEGF expression in vivo were also analyzed. Results: SC (≤2.5 μM) was safe both in vitro and in vivo. Intravitreal injection of SC restrained the formation of laser induced CNV in mice and decreased VEGF expression in the laser site of the retina/choroid complex. In vitro, SC inhibited VEGF-induced tube formation and endothelial cell migration by decreasing the phosphorylation of AKT, ERK1/2, and p38-MAPK in HRMECs. Conclusions: SC could inhibit laser-induced CNV formation via down-regulating VEGF expression and restrain the VEGF-induced tube formation and endothelial migration. Therefore, SC could be a potential candidate for the treatment of wet AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of severe blindness among the elderly in developed countries (Mitchell et al, 2018)
Choroidal neovascularization (CNV), the hallmark of wet AMD,is represented by pathological angiogenesis originating from choriocapillaris and breaking through Bruch’s membrane as well as RPE, resulting in the subretinal space leakage and sudden vision loss (Al-Zamil et al, 2017)
CCK8 assay was used to evaluate the cytotoxicity of Sanguinarine chloride (SC) toward human retinal microvascular endothelial cells (HRMECs)
Summary
Age-related macular degeneration (AMD) is the leading cause of severe blindness among the elderly in developed countries (Mitchell et al, 2018). Though the exact mechanism of AMD is still not clear, vascular endothelial growth factor (VEGF) is well accepted to play a crucial role in the angiogenesis formation (Bhutto and Lutty, 2012; van Lookeren Campagne et al, 2014). The current standard therapy for the treatment of wet-AMD is repeated intravitreal injections of antibodies against vascular endothelial growth factor (VEGF) (Aiello et al, 1995; Ferrara et al, 2006). Though it is effective in preventing and reducing neovascularization in some patients, it has limitations including the need for frequent intravitreal injection and inducement of macular disorders. The purpose of this study is to investigate the antiangiogenic effect of Sanguinarine chloride (SC) on models of age-related macular degeneration (AMD) both in vivo and in vitro
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