June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Assessment of the therapeutic value of phloroglucinol in Stargardt’s disease
Author Affiliations & Notes
  • Philippe Brabet
    Institute for Neurosciences of Montpellier, INSERM U1051, Montpellier, France
  • David Cia
    Laboratoire de Biophysique Neurosensorielle, UMR Inserm 1107, Clermont-Ferrand, France
  • Claire Vigor
    Institut des Biomolécules Max Mousseron (IBMM), UMR CNRS 5247, Montpellier, France
  • Nathalie Jacquemot
    Laboratoire de Biophysique Neurosensorielle, UMR Inserm 1107, Clermont-Ferrand, France
  • Benoit Lerat
    Institute for Neurosciences of Montpellier, INSERM U1051, Montpellier, France
  • Laurent Guillou
    Institute for Neurosciences of Montpellier, INSERM U1051, Montpellier, France
  • Celine Crauste
    Institut des Biomolécules Max Mousseron (IBMM), UMR CNRS 5247, Montpellier, France
  • Christian Hamel
    Institute for Neurosciences of Montpellier, INSERM U1051, Montpellier, France
  • Joseph Vercauteren
    Institut des Biomolécules Max Mousseron (IBMM), UMR CNRS 5247, Montpellier, France
  • Footnotes
    Commercial Relationships Philippe Brabet, None; David Cia, None; Claire Vigor, None; Nathalie Jacquemot, None; Benoit Lerat, None; Laurent Guillou, None; Celine Crauste, None; Christian Hamel, None; Joseph Vercauteren, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1949. doi:
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      Philippe Brabet, David Cia, Claire Vigor, Nathalie Jacquemot, Benoit Lerat, Laurent Guillou, Celine Crauste, Christian Hamel, Joseph Vercauteren; Assessment of the therapeutic value of phloroglucinol in Stargardt’s disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1949.

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

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Abstract

Purpose: Autosomal recessive Stargardt's disease is the most common cause of macular dystrophies due to mutations in ABCA4 gene. When transporter ABCA4 activity is impaired, all-trans retinal (atRAL) accumulates and triggers formation with phosphatidylethanolamine of A2-PE by carbonyl and oxidative stress. Daily photoreceptor outer segments (POS) phagocytosis by retinal pigment epithelium (RPE) leads to A2E accumulation, causing RPE death and progressive photoreceptor loss. Our goal is to design and select powerful chemicals against carbonyl and oxidative stress (anti-COS).

Methods: Phloroglucinol (benzene-1,3,5- triol) was first assessed for its efficacy as anti-COS. ARPE-19 cell line and rat RPE primary cultures were pre-incubated with phloroglucinol before incubation with oxidative (H2O2 and A2E) and carbonyl (atRAL) stressors. Cell viability was measured using tetrazolium compound (MTT) assay. Alternatively, phloroglucinol was co-incubated with atRAL. Test- tube experiments were carried out to inhibit the synthesis of A2E from atRAL and ethanolamine in the presence of phlorogucinol. Adducts formed between phloroglucinol and atRAL were identified by NMR and mass analysis.

Results: Treatment of RPE cells with phloroglucinol alone does not affect the cell viability. Exposure of RPE cells to stressors caused dose-dependent decreases in cell viability, whereas pretreatment with phloroglucinol significantly reduced the decline. Co-treatment of RPE cells with phloroglucinol and atRAL drastically prevented RPE cell death. In the presence of atRAL and ethanolamine, phloroglucinol led to complete inhibition of A2E synthesis.

Conclusions: Phloroglucinol has a dual action as anti-carbonyl stress and anti- oxidant in RPE cells. The proposed mechanism for the anti-carbonyl stress action is the trapping of all-trans retinal. Lower protection observed during pre-incubation compared to co-incubation suggests a low bioavailability of phoroglucinol.

Keywords: 726 stress response • 449 cell survival • 503 drug toxicity/drug effects  
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