Abstract
Age-related macular degeneration (AMD), a major cause of blindness in the elderly, is associated with oxidative stress, lipofuscin accumulation and retinal degeneration. The aim of this study was to determine if a 5-HT1A receptor agonist can reduce lipofuscin accumulation, reduce oxidative damage and prevent retinal cell loss both in vitro and in vivo. Autophagy-derived and photoreceptor outer segment (POS)-derived lipofuscin formation was assessed using FACS analysis and confocal microscopy in cultured retinal pigment epithelial (RPE) cells in the presence or absence of the 5-HT1A receptor agonist, 8-OH DPAT. 8-OH DPAT treatment resulted in a dose-dependent reduction in both autophagy- and POS-derived lipofuscin compared to control. Reduction in autophagy-induced lipofuscin was sustained for 4 weeks following removal of the drug. The ability of 8-OH DPAT to reduce oxidative damage following exposure to 200 µM H2O2 was assessed. 8-OH DPAT reduced superoxide generation and increased mitochondrial superoxide dismutase (MnSOD) levels and the ratio of reduced glutathione to the oxidized form of glutathione in H2O2-treated cells compared to controls and protected against H2O2-initiated lipid peroxidation, nitrotyrosine levels and mitochondrial damage. SOD2 knockdown mice, which have an AMD-like phenotype, received daily subcutaneous injections of either saline, 0.5 or 5.0 mg/kg 8-OH DPAT and were evaluated at monthly intervals. Systemic administration of 8-OH DPAT improved the electroretinogram response in SOD2 knockdown eyes of mice compared to knockdown eyes receiving vehicle control. There was a significant increase in the ONL thickness in mice treated with 8-OH DPAT at 4 months past the time of MnSOD knockdown compared to untreated controls together with a 60% reduction in RPE lipofuscin. The data indicate that 5-HT1A agonists can reduce lipofuscin accumulation and protect the retina from oxidative damage and mitochondrial dysfunction. 5-HT1A receptor agonists may have potential as therapeutic agents in the treatment of retinal degenerative disease.
Highlights
Age-related macular degeneration (AMD) is the major cause of blindness in the elderly in developed countries, with more than 1.7 million Americans over age 65 having visual impairment due to AMD [1]
In this study we report that the 5-HT1A agonist, 8-hydroxy-2(di-n-propylamino)-tetralin (8-OH DPAT), is able to reduce the accumulation of both autophagic-derived and photoreceptor outer segment-derived lipofuscin, increase antioxidant protection and reduce oxidative damage in cultured human retinal pigment epithelium (RPE) cells as well as being able to reduce lipofuscin accumulation and improve visual function in an animal model of AMD
Our results demonstrate the 5-HT1A receptor agonist, 8-OH DPAT, is able to protect the retina from degeneration by reducing oxidative damage
Summary
Age-related macular degeneration (AMD) is the major cause of blindness in the elderly in developed countries, with more than 1.7 million Americans over age 65 having visual impairment due to AMD [1]. Elevated levels of the age pigment lipofuscin and oxidative stress are associated with a variety of retinal degenerations including AMD, and there is considerable circumstantial evidence linking lipofuscin with the pathobiology of AMD [2,3,4,5,6]. Given the increasing evidence for lipofuscin involvement in AMD there is a growing interest in the development of therapeutic agents to both prevent lipofuscin formation and eliminate preexisting lipofuscin. These studies have primarily focused on slowing the retinoid cycle and reducing the accumulation of retinoid derivatives such as A2E in lipofuscin
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