Effects And Mechanisms Of Trehalose Derivative DMBT Against Wet Type Of Age-related Macular Degeneration

Age-related macular degeneration(AMD)is the leading cause of severe vision loss among elderly patients worldwide.Choroidal neovascularization(CNV)is the hallmark of late staged wet AMD,and is responsible for most of cases of blindness due to AMD.Human retinal photoreceptor cells and retinal pigment epithelium cells are separated from upper retinal blood vessels and are avascular.It receives oxygen and nutrients from the choroidal circulation.The retinal pigment epithelium(RPE),which has harrier characteristics prevents fluid from entering the outer retina but allows oxygen and nutrients to enter.Hypoxia micro-environment results in rising secretion of vascular endothelial growth factor(VEGF),which induces adjacent choroidal endothelial cells(CECs)proliferation,promotes CECs migration and plays an essential role in the regulation of the development and progression of wet AMD.Thus inhibiting the secretion of VEGF is the key to successful treatment.Trehalose derivative Brartemicin is isolated from(Actinomycete)Nonomuraea sp.metabolites by Japanese scientists Igarashi,which has stronger anti-invasion and metastasis ability on tumor cells with low toxicity.To search for better compound,a series of Brartemiein analogs were synthesized by Professor ZP Liu's group.After screening,DMBT,6,6'-bis(2,3-dimethoxybenzoyl)-a,a-D-trehalose,has been proven to suppress tumor mediated angiogenesis and metastasis by inhibiting endogenous production of VEGF in various tumor cells.But the effects of DMBT on CNV were not known.The objective of this study was to determine whether treatment with DMBT results in alleviating CNV process and to explore the possible underlying mechanisms in vitro and in vivo.In this study,MTT assay showed that no obvious inhibitory or cytotoxic effect of DMBT on ARPE-19 cells and RF/6A cells was found.DMBT could inhibit migration and tube formation of RF/6A cells under ARPE-19 hypoxia conditioned medium.DMBT could reduce lesion area in laser-induced CNV model mice.ELISA and Western blotting assay showed that DMBT markedly inhibited secretion of VEGF in vitro and in vivo.Furthermore,DMBT restrained ROS level under hypoxia via suppressing Nrf2/HO-1 pathway.In addition,Western blotting demonstrated that DMBT effectively suppressed hypoxia-induced the up-regulation of p-Akt,p-NF-?B,and HIF1?.In conclusion,these results suggested that DMBT could inhibit CNV by down-regulation of VEGF in retina,resulting from the inhibition of Akt/NF-?B/HIF 1? and ERK/Nrf2/HO-1/HIF1? pathway.DMBT might be a promising lead molecule for the anti-CNV and serve as a therapeutic agent to inhibit choroidal neovascularization.