Ilimaquinone inhibits neovascular age-related macular degeneration through modulation of Wnt/β-catenin and p53 pathways. (November 2020)

• Record Type: Journal Article
• Authors: Son, Younglim; Lim, Daehan; Park, Seoyoung; Song, Im-Sook; Kim, Joo-Hyun; Shin, Sora; Jang, Hoik; Liu, Kwang-Hyeon; O, Yuseok; Song, Gyu-Yong; Kang, Wonku; Cho, Yun-seok; Na, MinKyun; Chung, Hyewon; Oh, Sangtaek
• Is Part Of: Pharmacological research. Volume 161(2020)
• Publication Date: 2020-11
• Subjects: IQ ilimaquinone -- nAMD neovascular age-related macular degeneration -- RPE retinal pigment epithelium -- VEGF vascular endothelial growth factor -- CNV choroidal neovascularization -- TNF-α tumor necrosis factor-α -- NF-κB nuclear factor-κB -- EMT epithelial–mesenchymal transition -- HIF hypoxia-inducible factor -- bFGF basic fibroblast growth factor -- HUVECs human umbilical vein endothelial cells -- HUVSMCs human umbilical vein smooth muscle cells -- CEFO Cell Engineering for Origin -- FBS fetal bovine serum -- Wnt3a-CM Wnt3a-conditioned medium -- DAPI 4' 6-diamidino-2-phenylindole -- PI propidium iodide -- FA fluorescein angiography -- PBS phosphate-buffered saline -- CRTβ catenin response transcription -- PKD protein kinase D -- RLU relative light units; Neovascular age-related macular degeneration -- Ilimaquinone -- Wnt/β-catenin pathway -- p53 pathway; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105146
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Neovascular age-related macular degeneration (nAMD) is a common cause of irreversible vision loss in the elderly. Anti-vascular endothelial growth factor has been effective in treating pathological ocular neovascularization, but it has limitations including the need for repeated intraocular injections for the maintenance of therapeutic effects in most patients and poor or non-response to this agent in some patients. in vitro cellular studies were conducted using retinal pigment epithelial cell lines (ARPE-19 and hTERT-RPE1), human umbilical vein endothelial cells (HUVECs), and human umbilical vein smooth muscle cells (HUVSMCs). in vivo efficacy of ilimaquinone (IQ) was tested in laser-induced choroidal neovascularization mouse and rabbit models. Tissue distribution study was performed in male C57BL6/J mice. IQ, 4, 9-friedodrimane-type sesquiterpenoid isolated from the marine sponge, repressed the expression of angiogenic/inflammatory factors and restored the expression of E-cadherin in retinal pigment epithelial cells by inhibiting the Wnt/β-catenin pathway. In addition, it selectively inhibited proliferation and tube formation of HUVECs by activating the p53 pathway. Topical and intraperitoneal administration of IQ significantly reduced choroidal neovascularization in rabbits and mice with laser-induced choroidal neovascularization. Notably, IQ by the oral route of exposure was highly permeable to the eyes and suppressed abnormal vascular leakage by downregulation of β-catenin and stabilization of p53 in vivo . Our findings demonstrate that IQ functions through regulation of p53 and Wnt/β-catenin pathways with conceivable advantages over existing cytokine-targeted anti-angiogenic therapies.