Abstract
The accumulation of N-retinylidene-N-retinylethanolamine (A2E, a toxic by-product of the visual pigment cycle) in the retinal pigment epithelium (RPE) is a major cause of visual impairment in the elderly. Photooxidation of A2E results in retinal pigment epithelium degeneration followed by that of associated photoreceptors. Present treatments rely on nutrient supplementation with antioxidants. 9’-cis-Norbixin (a natural diapocarotenoid, 97% purity) was prepared from Bixa orellana seeds. It was first evaluated in primary cultures of porcine retinal pigment epithelium cells challenged with A2E and illuminated with blue light, and it provided an improved photo-protection as compared with lutein or zeaxanthin. In Abca4-/- Rdh8-/- mice (a model of dry AMD), intravitreally-injected norbixin maintained the electroretinogram and protected photoreceptors against light damage. In a standard rat blue-light model of photodamage, norbixin was at least equally as active as phenyl-N-tert-butylnitrone, a free radical spin-trap. Chronic experiments performed with Abca4-/- Rdh8-/- mice treated orally for 3 months with norbixin showed a reduced A2E accumulation in the retina. Norbixin appears promising for developing an oral treatment of macular degeneration. A drug candidate (BIO201) with 9’-cis-norbixin as the active principle ingredient is under development, and its potential will be assessed in a forthcoming clinical trial.
Highlights
In developed countries, age-related macular degeneration (AMD) is the major cause of blindness in the elderly [1]
Dry AMD is characterized by retinal deformation owing to the local accumulation of waste deposits, photoreceptors degenerate in small areas, which increase in size, leading to advanced dry AMD
In order to mimic lipofuscin-mediated photooxidation in vivo we developed an acute model of phototoxicity using porcine primary retinal pigment epithelium (RPE) cells loaded with 30 μM A2E and illuminated with blue light (Fig 2A)
Summary
AMD is the major cause of blindness in the elderly [1]. Dry AMD, the most frequent form, is a slowly evolving pathology. Dry AMD is characterized by retinal deformation owing to the local accumulation of waste deposits, photoreceptors degenerate in small areas, which increase in size, leading to advanced dry AMD (geographic atrophy). Photoreceptor death in the central part of the retina (the macula) is responsible for the loss of high-resolution colour vision. It follows the death of the retinal pigment epithelium (RPE) cells [2], which have major roles in the visual pigment cycle and the phagocytosis of shed.
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