title: An arylidene-thiazolidinedione derivative, GPU-4, without PPARγ activation, reduces retinal neovascularization.
abstract: Retinal angiogenesis is a leading cause of blindness, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Vascular endothelial growth factor (VEGF) is one of the major angiogenesis factors, and induces endothelial cell proliferation and migration. VEGF stimulates NADPH oxidase to produce reactive oxygen species (ROS), and ROS induce the transcription factors and genes involved in angiogenesis. In the present study, we demonstrated that GPU-4, 5-arylidene-2,4-thiazolidinedione derivative, demonstrates anti-angiogenic activity regarding human retinal microvascular endothelial cells (HRMECs) and retinal neovascularization in a mouse model of retinopathy of prematurity. GPU-4 inhibited the VEGF-induced radicals, proliferation, and migration in HRMECs without a PPARγ-mediated effect. Furthermore, systemic administration of GPU-4 inhibited the development of retinal neovascularization in a murine oxygen-induced retinopathy model but did not exert revascularization of the capillary-free area, which shows normal physiological revascularization. These findings indicate that GPU-4 suppressed in vitro and in vivo retinal neovascularization partly by a radical scavenging effect, suggesting that GPU-4 might be a potential therapeutic agent candidate for proliferative diseases of the retinal vasculature.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Nakamura
authors.forename: Kei
authors.initials: K
authors.lastname: Hayashi
authors.forename: Haruka
authors.initials: H
authors.lastname: Takizawa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Murase
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D047495:PPAR gamma / Q000378:metabolism*; D012161:Retinal Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C569195:5-(4-hydroxy-3,5-dimethylbenzylidene)thiazolidine-2,4-dione; D020533:Angiogenesis Inhibitors; D001597:Benzylidene Compounds; D016166:Free Radical Scavengers; D047495:PPAR gamma; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione