Norbixin Protects Retinal Pigmented Epithelium Cells and Photoreceptors against A2E-Mediated Phototoxicity In Vitro and In Vivo

PLoS One. 2016 Dec 16;11(12):e0167793. doi: 10.1371/journal.pone.0167793. eCollection 2016.

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.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Alcohol Oxidoreductases / genetics
  • Animals
  • Bixaceae / chemistry
  • Carotenoids / administration & dosage*
  • Carotenoids / pharmacology
  • Cells, Cultured
  • Disease Models, Animal
  • In Vitro Techniques
  • Intravitreal Injections
  • Macular Degeneration / chemically induced
  • Macular Degeneration / drug therapy*
  • Macular Degeneration / genetics
  • Macular Degeneration / metabolism
  • Mice
  • Mice, Knockout
  • Photoreceptor Cells, Vertebrate / drug effects*
  • Plant Extracts / administration & dosage
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Rats
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / drug effects*
  • Retinoids / adverse effects*
  • Swine

Substances

  • A2-E (N-retinylidene-N-retinylethanolamine)
  • ATP-Binding Cassette Transporters
  • Abca4 protein, mouse
  • Plant Extracts
  • Retinoids
  • Carotenoids
  • norbixin
  • Alcohol Oxidoreductases
  • Rdh8 protein, mouse

Grants and funding

This manuscript results from a collaborative work between one public laboratory (Institut de la Vision) and two private companies (Biophytis and Iris Pharma). Financial support came from the private companies, a European FEDER grant (PRESAGE 41583) and a grant from the City of Paris (n° 2012 DDEEES 103G). The experimental work was shared between the three organisations. Biophytis and Iris Pharma participated to the design and realization of the experiments. They declare, however, that their potential commercial interests had no impact on the scientific conduct of the study or the analysis/interpretation of data. The grant providers (FEDER and City of Paris) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The City of Paris grant supported in particular the salaries of the three engineers (EM, EB, LL). PPE and LF are employees of Iris Pharma, while CB, LG, SV and RL are employees of Biophytis.