Ursodeoxycholic Acid Halts Pathological Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy.

Menaka C Thounaojam,Manuela Bartoli,Ravirajsinh N Jadeja,Shubhra Rajpurohit,Diana R Gutsaeva,Pamela M Martin,Brian K Stansfield

doi:10.3390/jcm9061921

Menaka C Thounaojam, Manuela Bartoli + Show 5 more

Open Access

https://doi.org/10.3390/jcm9061921

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Abstract

Retinopathy of prematurity (ROP) is the leading cause of blindness in infants. We have investigated the efficacy of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine and glycine conjugated derivatives tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) in preventing retinal neovascularization (RNV) in an experimental model of ROP. Seven-day-old mice pups (P7) were subjected to oxygen-induced retinopathy (OIR) and were treated with bile acids for various durations. Analysis of retinal vascular growth and distribution revealed that UDCA treatment (50 mg/kg, P7–P17) of OIR mice decreased the extension of neovascular and avascular areas, whereas treatments with TUDCA and GUDCA showed no changes. UDCA also prevented reactive gliosis, preserved ganglion cell survival, and ameliorated OIR-induced blood retinal barrier dysfunction. These effects were associated with decreased levels of oxidative stress markers, inflammatory cytokines, and normalization of the VEGF–STAT3 signaling axis. Furthermore, in vitro tube formation and permeability assays confirmed UDCA inhibitory activity toward VEGF-induced pro-angiogenic and pro-permeability effects on human retinal microvascular endothelial cells. Collectively, our results suggest that UDCA could represent a new effective therapy for ROP.

Highlights

Retinopathy of prematurity (ROP) is an ocular pathology affecting premature babies and is the leading cause of preventable blindness in children [1,2,3]
ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), and glycoursodeoxycholic acid (GUDCA) are the most widely used secondary conjugated Bile acids (BA) for pharmacological treatments; we evaluated the effects of these BA on retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR)
Treatments of OIR mice with GUDCA and TUDCA that were used at the same doses and for the same treatment times failed to show any significant change in neovascular area (Figure 1E) or avascular areas (Figure 1F) when compared to untreated OIR mice

Summary

Introduction

Retinopathy of prematurity (ROP) is an ocular pathology affecting premature babies and is the leading cause of preventable blindness in children [1,2,3]. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are used to halt retinal neovascularization (RNV) in the most advanced stages of ROP [8,9,10] All of these therapeutic approaches involve surgical procedures with harmful side effects including significant loss of visual field, glaucoma, and others [8,9,10,11]. Despite encouraging pre-clinical studies, dietary supplementation with omega-3 polyunsaturated fatty acid (PUFA) in premature babies has been shown to partially prevent the progression of ROP only to the most severe stages [12]. Therapies for this sight-threatening disease are still needed and, ideally, should halt abnormal vascularization without affecting normal vasculogenesis of the postnatal developing retina

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