An Arylidene-Thiazolidinedione Derivative, GPU-4, without PPARγ Activation, Reduces Retinal Neovascularization

Shinsuke      Nakamura; Kei      Hayashi; Haruka      Takizawa; Tetsuji      Murase; Kazuhiro      Tsuruma; Masamitsu      Shimazawa; Hiroki      Kakuta; Hideko      Nagasawa; Hideaki      Hara

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.

Keywords: Anti-oxidative effect, human retinal microvascular endothelial cell, oxygen-induced retinopathy model, reactive oxygen species, thiazolidinedione, vascular endothelial growth factor, peroxisome proliferators-activated receptor gamma (PPARg), mitogen-activated protein kinase (MAPK)