title: Norbixin Protects Retinal Pigmented Epithelium Cells and Photoreceptors against A2E-Mediated Phototoxicity In Vitro and In Vivo.
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.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, Paris, France.
authors.forename: Valérie
authors.identifier: http://orcid.org/0000-0003-0454-0154
authors.initials: V
authors.lastname: Fontaine
authors.affiliation: Sorbonne Universités, UPMC Univ Paris, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Monteiro
authors.affiliation: Sorbonne Universités, UPMC Univ Paris, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, Paris, France.
authors.forename: Elena
authors.initials: E
authors.lastname: Brazhnikova
authors.affiliation: Sorbonne Universités, UPMC Univ Paris, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, Paris, France.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Lesage
authors.affiliation: Biophytis, Parc BIOCITECH, 102 Avenue Gaston Roussel, Romainville, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Balducci
authors.affiliation: Biophytis, Parc BIOCITECH, 102 Avenue Gaston Roussel, Romainville, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Guibout
authors.affiliation: IRIS-Pharma, Les Nertières, Allée Hector Pintus, La Gaude, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Feraille
authors.affiliation: IRIS-Pharma, Les Nertières, Allée Hector Pintus, La Gaude, France.
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Elena
authors.affiliation: Sorbonne Universités, UPMC Univ Paris, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Biophytis, Parc BIOCITECH, 102 Avenue Gaston Roussel, Romainville, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Veillet
authors.affiliation: Biophytis, Parc BIOCITECH, 102 Avenue Gaston Roussel, Romainville, France.
authors.forename: René
authors.initials: R
authors.lastname: Lafont
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000818:Animals; D031212:Bixaceae / Q000737:chemistry; D002338:Carotenoids / Q000008:administration & dosage* / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects*; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects*; D012176:Retinoids / Q000009:adverse effects*; D013552:Swine
chemical_list: D018528:ATP-Binding Cassette Transporters; D000429:Alcohol Oxidoreductases; D002338:Carotenoids; D010936:Plant Extracts; D012176:Retinoids; C112040:A2-E (N-retinylidene-N-retinylethanolamine); C512841:Abca4 protein, mouse; C099823:norbixin; C525880:HSD17B6 protein, mouse