title: Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types.
abstract: The development of choroidal neovascularization (CNV) is a critical step in the pathogenesis of age-related macular degeneration (AMD), a vision-threatening disease. In this study, we used a mouse model of AMD to study the protective effects of resveratrol (RSV) supplementation against CNV as well as the underlying molecular mechanisms. Mice were orally pretreated with RSV daily for 5 days. On the fifth day, the mice underwent laser photocoagulation to induce CNV. One week after laser treatment, CNV volume was significantly lower in the RSV-treated mice compared with vehicle-treated animals. In addition, RSV treatment significantly inhibited macrophage infiltration into the retinal pigment epithelium (RPE)-choroid and suppressed the expression of inflammatory and angiogenic molecules, including vascular endothelial growth factor, monocyte chemotactic protein-1 and intercellular adhesion molecule-1. Importantly, RSV prevented the CNV-induced decrease in activated AMP-activated protein kinase and increase in activated nuclear factor-κB in the RPE-choroid complex. The regulatory effects of RSV on these molecules were confirmed in RPE, microvascular endothelial and macrophage cell lines. Inhibition of macrophage infiltration by RSV was confirmed by in vitro scratch and migration assays. RSV suppressed CNV development, reducing the levels of multiple cytokines secreted from several cell types and inhibiting macrophage migration. The direct effects of RSV on each cell type were confirmed in vitro. Although further studies are needed, RSV could potentially be applied in the clinic to prevent CNV development in AMD.
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nagai
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan. Electronic address: ozawa@a5.keio.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D013267:Stilbenes; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol
keywords: AMPK; Inflammation; Macrophage; Neovascularization; Resveratrol; Retina