Retinal pigment epithelium pathology in age-related macular degeneration: mitigation with melatonin

Approximately 1.5 million Americans over the age of 40 suffer from vision-threatening age-related macular degeneration (AMD), a number expected to rise with aging demographics. AMD exists in two defined forms: dry (non-exudative) which accounts for up to 90% of cases, and wet (exudative). Dry AMD is characterized by the slow buildup of drusen under the retina, eventually leading to geographical atrophy. Wet AMD involves vascular endothelial growth factor (VEGF)-induced blood vessel formation from the choriocapillaris into the subretinal space, a process referred to as neovascularization. These newly formed blood vessels leak fluid into the subretinal space leading to atrophy of the retinal pigment epithelium (RPE) and associated photoreceptors. Despite clinical distinctions, dry and wet AMD share overlapping pathophysiological features, marked by degeneration of the RPE and the overlying photoreceptors. A major feature of the RPE and photoreceptors are their high metabolically activity and their large numbers of mitochondria, which generate reactive oxygen species (ROS) during ATP production. ROS-induced oxidative stress damages lipids, proteins and DNA, resulting in cellular degradation which contributes to AMD. Because of the elevated oxidative stress levels, antioxidants which neutralize ROS are often recommended as a treatment for AMD. A major objective of this review is to examine the role of melatonin, a powerful and multifunctional antioxidant, in altering the trajectory of AMD progression. Melatonin is synthesized in the RPE and photoreceptors of young individuals but its expression declines with age. As shown in an epidemiological report, its loss contributes to age-related degeneration of the RPE and photoreceptors. Moreover, melatonin inhibits VEGF, suggesting that it would be useful as a treatment for wet AMD. This review explores melatonin-mediated protective mechanisms in the retina, a likely mechanistic basis for the already published findings showing that melatonin use by humans is associated with delayed AMD, and potential clinical applications.