Role of macular xanthophylls in prevention of common neovascular retinopathies: Retinopathy of prematurity and diabetic retinopathy

Highlights

• ROP and diabetic retinopathy (DR) are important causes of blindness.

• Dietary lutein and zeaxanthin are inversely associated with risks of ROP and DR.

• Xanthophylls modulate oxidative stress and inflammation in ROP and DR progression.

• More research is needed to establish the efficacy of xanthophylls in retinopathy.

Abstract

Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are important causes of blindness among children and working-age adults, respectively. The development of both diseases involves retinal microvascular degeneration, vessel loss and consequent hypoxic and inflammatory pathologic retinal neovascularization. Mechanistic studies have shown that oxidative stress and subsequent derangement of cell signaling are important factors in disease progression. In eye and vision research, role of the dietary xanthophyll carotenoids, lutein and zeaxanthin, has been more extensively studied in adult onset macular degeneration than these other retinopathies. These carotenoids also may decrease severity of ROP in preterm infants and of DR in working-age adults. A randomized controlled clinical trial of carotenoid supplementation in preterm infants indicated that lutein has functional effects in the neonatal eye and is anti-inflammatory. Three multicenter clinical trials all showed a trend of decreased ROP severity in the lutein supplemented group. Prospective studies on patients with non-proliferative DR indicate serum levels of lutein and zeaxanthin are significantly lower in these patients compared to normal subjects. The present review describes recent advances in lutein and zeaxanthin modulation of oxidative stress and inflammation related to ROP and DR and discusses potential roles of lutein/zeaxanthin in preventing or lessening the risks of disease initiation or progression.

Introduction

Retinal neovascularization (NV)¹ from ischemia-induced retinopathy are common causes of blindness in children (retinopathy of prematurity, ROP) and working-age adults (diabetic retinopathy, DR) in the developed world. Ischemic retinopathies are characterized by microvascular degeneration and retinal ischemia, which can lead to secondary aberrant neovascularization, hemorrhages and blindness [1], [2], [3]. This pathologic angiogenesis could be prevented either by direct inhibition of the pathologic NV or by reducing retinal vessel loss, thus, decreasing the hypoxic stimulus that drives the NV. Current therapeutic strategies for ischemic retinopathies have focused on the former approach of inhibiting later stages of pathologic NV. There is great potential in the alternative strategy of reducing vessel loss or promoting normal vascular repair, thereby reducing the hypoxic stimulus that drives NV [4], [5], [6]. Such a strategy could result in reducing retinal vascular degeneration, increasing retinal revascularization, or the combination of both. It is, therefore, of great benefit to learn more about the factors and mechanisms that govern the extent of vessel loss and normal vascular regrowth in ischemic retinopathies.

In human retina, two vascular systems (retinal and choroidal) provide blood supply to the highly oxygen-consuming retinal layers. The retinal vascular system provides oxygen and nutrients to the inner retina, whereas the choroidal vasculature supplies the outer retina [3]. In ROP, a delay in physiologic retinal vascular development in preterm infants, suppression of growth factors due to hyperoxia and increase in metabolic demand is associated with hypoxic retinal injury [7]. The hypoxic retina stimulates expression of oxygen-regulated proangiogenic factors, which stimulates retinal NV with sprouting of abnormal vessels from the retina into the vitreous [8], [9]. In diabetes, elevated blood glucose and decrease in blood flow result in hyperglycemia and hypoxia in the retina [10], [11].

The retina is highly susceptible to oxidative damage by reactive oxygen species (ROS). During pathological conditions, such as retinal ischemia, the imbalance between the production of ROS and the ability to scavenge these ROS by endogenous antioxidant systems is exaggerated. ROS triggers several signaling pathways, affects DNA and lipids inside the cell, and subsequently leads to cell death. Antioxidants that can inhibit or prevent the oxidative processes can protect retinal cells from oxidative damage. Antioxidants inhibit microvascular degeneration in animal models of DR [12], [13] and oxygen-induced retinopathy (OIR) [14], [15]. Recent clinical trials of lutein supplementation in term [16] and preterm infants point to lutein functional effects in the neonatal eye [17].

The carotenoids, lipophilic pigments, are important antioxidants, anti-inflammatory agents and regulators of development, reproduction, cellular differentiation and vision protection. They are characterized by an extended conjugated π-electron system that can only be synthesized by plants and microorganisms. Of the >700 described natural carotenoids, approximately 50–60 are typically consumed in the human diet, but only 15–20 are usually detected in human serum and tissues [18], including α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin. Of these, the xanthophylls (lutein and zeaxanthin) account for 20–30% of total carotenoids in human serum but 80–90% of the total carotenoids in the human retina [19]. In early primate development, lutein is the predominant retinal carotenoid. Over time, zeaxanthin levels rise, partly due to conversion of lutein to zeaxanthin. Meso-zeaxanthin, a specific lutein metabolite localized in the retina, has not been detected elsewhere in the body [20]. These xanthophylls are most dense at the center of the fovea in the yellowish pigmented area called the macula lutea and are referred to as macular pigment [21], [22]. The macular pigment is tissue protective, acting via antioxidant, anti-inflammatory and light-screening properties [23], [24].

Low systemic and retinal levels of lutein and zeaxanthin are adversely associated with the risk of age-related macular disease (AMD), ROP and DR [25], [26], [27], [28], [29]. Nevertheless, the molecular mechanisms underlying xanthophyll actions in the retina still remain elusive and whether dietary lutein/zeaxanthin can prevent or lessen severity of ROP and DR in practice remains somewhat inconclusive. To date, the majority of the evidence on protective effects of lutein and zeaxanthin in visual health has addressed AMD and cataract. In this review, we describe various aspects of ROP and DR pathogenesis and discuss the potential role of lutein and zeaxanthin in these common neovascular retinopathies of younger individuals.