The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration

Abstract

The blood retinal barrier (BRB) is a fundamental eye component, whose function is to select the flow of molecules from the blood to the retina and vice-versa, and its integrity allows the maintenance of a finely regulated microenvironment. The outer BRB, composed by the choriocapillaris, the Bruch's membrane, and the retinal pigment epithelium, undergoes structural and functional changes in age-related macular degeneration (AMD), the leading cause of blindness worldwide. BRB alterations lead to retinal dysfunction and neurodegeneration. Several risk factors have been associated with AMD onset in the past decades and oxidative stress is widely recognized as a key factor, even if the exact AMD pathophysiology has not been exactly elucidated yet. The present review describes the BRB physiology, the BRB changes occurring in AMD, the role of oxidative stress in AMD with a focus on the outer BRB structures. Moreover, we propose the use of cerium oxide nanoparticles as a new powerful anti-oxidant agent to combat AMD, based on the relevant existing data which demonstrated their beneficial effects in protecting the outer BRB in animal models of AMD.

Keywords: age-related macular degeneration; blood retinal barrier; oxidative stress; physiology.

Figure 1

Schematic illustration of the blood-retinal barrier (BRB) structure. (A) The outer BRB insulates the outer retina from the bloodstream deriving from the choriocapillaris (CC), whose endothelium shows multiple fenestrations (a). The molecules reach the neuroretina through the Bruch’s Membrane (BM), composed of five layers, which forms a size-selective barrier (a’), and through the retinal pigment epithelium (RPE), characterized by tight junctions (a’’). (B) The inner BRB insulates the inner retina from the retinal vasculature, composed by a deep, intermediate, and superficial plexus; the endothelial cells of the retinal vessels form an effective barrier because of the presence of tight junctions among them (b).

Figure 2

Schematic illustration of the events occurring in the outer BRB due to oxidative stress in age-related macular degeneration (AMD). All the risk factors for AMD induce oxidative stress burden, which affects the three components of the outer BRB. The effects of oxidative stress on the CC/BM/RPE complex culminates in a vicious cycle, which in turn induces further oxidative stress (red arrows). In addition, the induced damaging events of each BRB component inexorably affects the function and structure of the others (black arrows). All of these events highlight the finely balanced nature of the outer BRB, in which any alterations trigger a series of sequential events, which ultimately induce BRB breakdown and AMD. A detailed description about how oxidative stress affects the outer BRB in AMD is reported in the following paragraphs.

Figure 3

Confocal images of retinal pigment epithelium (RPE) in rats. Left: RPE from a healthy albino Sprague Dawley rat. The RPE is constituted by a homogeneous monolayer of joined epithelial cells displaying a hexagonal morphology. Right: RPE from a light damaged albino Sprague Dawley rat. The RPE structure appears clearly altered, cell junctions are lacking (red arrow), the onset of multinucleation suggests epithelial-mesenchymal transition (white arrows), and some cells have degenerated. Images were acquired by Leica TCS SP5 confocal microscope; 60× magnification. Green: phalloidin staining; blue: bisbenzimide nuclear dye; scale bar: 50 µm.