Aucuba japonica extract inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy, with its bioactive components preventing VEGF-induced retinal vascular hyperpermeability.

Eunsoo Jung,Junghyun Kim,Su-Bin Park,Woo Kwon Jung,Hyung Rae Kim

doi:10.1002/fsn3.1590

Abstract

Neovascularization in the retina is common pathophysiology of diabetic retinal microvasculopathy and exudative macular degeneration. Our study assessed the inhibitory activity of an ethanol‐based extract of Aucuba japonica (AJE) on abnormal angiogenesis in the retina with a hyperoxia‐induced neovascular retinopathy model. The inhibitory effects of aucubin, quercetin, and kaempferol, bioactive compounds, from A. japonica, on retinal vascular hyperpermeability were also examined. On the 7th postnatal day (P7), the C57BL/6 pups were exposed to a hyperoxic environment with 75% oxygen to develop the experimental angiogenesis in retinas. On the 12th postnatal day (P12), the pups were then returned to the normal atmospheric pressure of oxygen. From P12 to P16, the administration was intraperitoneal. The dose per day was 250 mg per kg weight. Retinal neovascularization was measured with retinal flat mounts prepared on P17. We also measured the vascular leakage mediated by the vascular endothelial growth factor (VEGF) in retinas. Mice treated with AJE had markedly smaller neovascular lesions, in comparison with vehicle‐administered mice. AJE downregulated the expression of both VEGF protein and mRNA. In addition, aucubin, quercetin, and kaempferol ameliorated VEGF‐induced retinal vascular leakage. The results of our study suggest that AJE is a potent antiangiogenic substance. AJE could also serve as a therapeutic agent for abnormal growth of vessels in the retina in patients with ischemic retinopathy. The bioactive compounds of AJE may be responsible for its antiangiogenic abilities.

Highlights

Advanced retinal neovascularization causes visual impairment and a complete loss of sight in a significant proportion of the elderly over 65 years of age (Solomon, Lindsley, Vedula, Krzystolik, & Hawkins, 2019)
We examined the antiangiogenic activities of an ethanolic extract of A. japonica (AJE) in an oxygen-induced ischemic retinopathy (OIR) model
Suppression of vascular endothelial growth factor (VEGF) expression occurred in OIR model in the hyperoxic phase (P7-P12) (Stone et al, 1996)

Summary

| INTRODUCTION

Advanced retinal neovascularization causes visual impairment and a complete loss of sight in a significant proportion of the elderly over 65 years of age (Solomon, Lindsley, Vedula, Krzystolik, & Hawkins, 2019). Anti-VEGF drugs, such as bevacizumab, aflibercept, and ranibizumab, have been administered intravitreally in clinical trials. It is noteworthy that the intravitreal administration of anti-VEGF agents has been associated with adverse effects (Diago et al, 2009; Fintak et al, 2008). When anti-VEGF agents are administered intravitreally repeatedly, ocular complications, such as endophthalmitis, traumatic cataracts, ocular inflammation, retinal detachment, intraocular pressure elevation, and vitreous hemorrhage, can occur at a high incidence (Falavarjani & Nguyen, 2013). The antiangiogenic abilities of A. japonica on the neovascular retinal diseases have not been described in reports, according to our research. The ability of aucubin, kaempferol, and quercetin to inhibit retinal vascular hyperpermeability stimulated by administering exogenous VEGF intravitreally in rats was assessed

| MATERIALS AND METHODS

| RESULTS AND DISCUSSION

| CONCLUSION