Biomedicine & Pharmacotherapy (Sep 2023)
Xanthine derivative KMUP-1 ameliorates retinopathy
Abstract
Retinal neovascularization (RNV) and cell apoptosis observed in retinopathy are the most common cause of vision loss worldwide. Increasing vascular endothelial growth factor (VEGF), which was driven by hypoxia or inflammation, would result in RNV. This study investigated the anti-inflammatory and anti-apoptotic xanthine-based derivative KMUP-1 on hypoxia-induced conditions in vitro and in vivo. In the oxygen-induced retinopathy animal model, KMUP-1 mitigated vaso-obliteration and neovascularization. In the cell model of hypoxic endothelium cultured at 1% O2, KMUP-1 inhibited endothelial migration and tube formation and had no cytotoxic effect on cell growth. Upregulation of pro-angiogenic factors, HIF-1α and VEGF, and pro-inflammatory cytokines, IL-1β and TNF-α, expression in the retinal-derived endothelial cells, RF/6 A cells, upon hypoxia stimulation, was suppressed by KMUP-1 treatment. RF/6 A cells treated with KMUP-1 showed a reduction of PI3K/Akt, ERK, and RhoA/ROCKs signaling pathways and induction of protective pathways such as eNOS and soluble guanylyl cyclase at 1% O2. Furthermore, KMUP-1 decreased the expression of VEGF, ICAM-1, TNF-α, and IL-1β and increased the BCL-2/BAX ratio in the oxygen-induced retinopathy mouse retina samples. In conclusion, the results of this study suggest that KMUP-1 has potential therapeutic value in retinopathy due to its triple effects on anti-angiogenesis, anti-inflammation, and anti-apoptosis in hypoxic endothelium.
