June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
3-Deoxyanthocyanidins protect efficiently RPE cells and photoreceptors against A2E-mediated phototoxicity
Author Affiliations & Notes
  • Pierre Dilda
    Biophytis, Paris, France
  • Laetitia Lesage
    Institut de la Vision, Paris, France
  • Louis Guibout
    Biophytis, Paris, France
  • Elena Brazhnikova
    Institut de la Vision, Paris, France
  • Christine Balducci
    Biophytis, Paris, France
  • Anne-Sophie Foucault
    Biophytis, Paris, France
  • Jose Alain Sahel
    Institut de la Vision, Paris, France
  • Stanislas Veillet
    Biophytis, Paris, France
  • René Lafont
    Biophytis, Paris, France
  • Valerie Fontaine
    Institut de la Vision, Paris, France
  • Footnotes
    Commercial Relationships   Pierre Dilda, Biophytis (E); Laetitia Lesage, None; Louis Guibout, Biophytis (E); Elena Brazhnikova, None; Christine Balducci, Biophytis (E); Anne-Sophie Foucault, Biophytis (E); Jose Sahel, Biophytis (P), Biophytis (S); Stanislas Veillet, Biophytis (E), Biophytis (I), Biophytis (P); René Lafont, Biophytis (E), Biophytis (P), Biophytis (I); Valerie Fontaine, Biophytis (P), Biophytis (F)
  • Footnotes
    Support  European Grant FEDER: PRESAGE41583; Ville de Paris: 2012 DDEEES 103G
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1965. doi:
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      Pierre Dilda, Laetitia Lesage, Louis Guibout, Elena Brazhnikova, Christine Balducci, Anne-Sophie Foucault, Jose Alain Sahel, Stanislas Veillet, René Lafont, Valerie Fontaine; 3-Deoxyanthocyanidins protect efficiently RPE cells and photoreceptors against A2E-mediated phototoxicity
      . Invest. Ophthalmol. Vis. Sci. 2017;58(8):1965.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Various eye diseases are linked to the accumulation of lipofuscins in the retinal pigment epithelium (RPE) cells, such as AMD or Stargardt disease. It is generally accepted that the accumulation of lipofuscins (containing trans-retinal derivatives: A2E, RAL-di) is involved in the senescence of the RPE. Prevention or treatments currently based on food supplements display only limited therapeutic efficacy. We have conducted extensive studies on natural and synthetic anthocyanidins for their photo-protection of RPE cells in order to establish structure activity relationship (SAR), with the aim of identifying particularly active chemical structures.

Methods : Nineteen natural compounds (16 anthocyanidins + 3 anthocyanins) and 12 synthetic 3,5-dideoxy-anthocyanidins were screened using an in vitro photo-toxicity assay employing primary cultures of porcine RPE cells challenged with A2E then blue light illumination (430 nm) followed by a cell viability test (n=4). The best compounds were further studied in vivo in blue light-challenged Abca4-/-Rdh8-/- mice (n=13), which accumulate A2E, due to an impaired visual pigment cycle. Functional (electroretinogram; ERG) and histological (photoreceptor layers) consequences of intra vitreous drug treatments were measured. Statistical analysis: ANOVA and Dunnett’s tests.

Results : In vitro assays demonstrated the absence of anthocyanins’ photo-protective activity. Among natural anthocyanidins, those lacking the 3–OH, including notably diosmetinidin, displayed highly significant protective activities at 20 µM (p< 0.001; ≥ 89% cell survival vs only 30% in control). Similarly, several synthetic 3,5-dideoxy-anthocyanidins were highly active. In both cases, the activity was strongly dependent on the nature and position of substituents (-OH and –OMe). In vivo, ERG measurements showed that diosmetinidin (120 µM) significantly prevented the decrease of A wave amplitude by 24% (p<0.01) and B wave amplitude by 36% (p<0.001). At the histological level, diosmetinidin treatment strongly protected the photoreceptor cells in the central retina with 4.82 ± 0.17 in the drug injected eyes vs 0.71 ± 0.10 cell layers in the control eyes (p< 0.001).

Conclusions : Taken together, these SAR studies demonstrated by both in vitro and in vivo approaches the potential of the 3-deoxy- and 3,5-dideoxy-anthocyanidins for retina photoprotection.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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