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• Research Paper Volume 13, Issue 18 pp 22040-22058

  A2E-induced inflammation and angiogenesis in RPE cells in vitro are modulated by PPAR-α, -β/δ, -γ, and RXR antagonists and by norbixin

  Relevance score: 4.2663426

  Valérie Fontaine, Mylène Fournié, Elodie Monteiro, Thinhinane Boumedine, Christine Balducci, Louis Guibout, Mathilde Latil, José-Alain Sahel, Stanislas Veillet, Pierre J. Dilda, René Lafont, Serge Camelo

  Keywords: N-retinylidene-N-retinylethanolamine (A2E), norbixin, peroxisome proliferator-activated receptor (PPAR), retinal pigment epithelium (RPE), retinoic X receptor (RXR)

  Published in Aging on September 20, 2021

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  N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing angiogenesis and inflammation. A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-α. Here we show that A2E binds and transactivates also peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR). 9’-cis-norbixin, a di-apocarotenoid is also a ligand of these nuclear receptors (NR). Norbixin inhibits PPAR and RXR transactivation induced by A2E. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-κB and AP-1 transactivation and mRNA expression of the inflammatory interleukins (IL) -6 and -8 and of vascular endothelial growth factor (VEGF) enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression in response to A2E. Selective PPAR-α, -β/δ and –γ antagonists inhibit the expression of IL-6 and IL-8 while only the antagonist of PPAR-γ inhibits the transactivation of NF-κB following A2E exposure. In addition, a cocktail of all three PPARs antagonists and also HX531, an antagonist of RXR reproduce norbixin effects on inflammation. Altogether, A2E’s deleterious biological effects could be inhibited through PPAR and RXR regulation. Moreover, the modulation of these NR by norbixin may open new avenues for the treatment of AMD.

• Research Paper Volume 12, Issue 7 pp 6151-6171

  Systemic administration of the di-apocarotenoid norbixin (BIO201) is neuroprotective, preserves photoreceptor function and inhibits A2E and lipofuscin accumulation in animal models of age-related macular degeneration and Stargardt disease

  Relevance score: 7.6768913

  Valérie Fontaine, Elodie Monteiro, Mylène Fournié, Elena Brazhnikova, Thinhinane Boumedine, Cécile Vidal, Christine Balducci, Louis Guibout, Mathilde Latil, Pierre J. Dilda, Stanislas Veillet, José-Alain Sahel, René Lafont, Serge Camelo

  Keywords: norbixin, retinal function, A2E, AMD, Stargardt disease

  Published in Aging on April 7, 2020

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  Atrophic A\age-related macular degeneration (AMD) and Stargardt disease (STGD) are major blinding diseases affecting millions of patients worldwide, but no treatment is available. In dry AMD and STGD oxidative stress and subretinal accumulation of N-retinylidene-N-retinylethanolamine (A2E), a toxic by-product of the visual cycle, causes retinal pigment epithelium (RPE) and photoreceptor degeneration leading to visual impairment. Acute and chronic retinal degeneration following blue light damage (BLD) in BALB/c mice and aging of Abca4^-/- Rdh8^-/- mice, respectively, reproduce features of AMD and STGD. Efficacy of systemic administrations of 9'-cis-norbixin (norbixin), a natural di-apocarotenoid, prepared from Bixa orellana seeds with anti-oxidative properties, was evaluated during BLD in BALB/c mice, and in Abca4^-/- Rdh8^-/- mice of different ages, following three experimental designs: “preventive”, “early curative” and “late curative” supplementations. Norbixin injected intraperitoneally in BALB/c mice, maintained scotopic and photopic electroretinogram amplitude and was neuroprotective. Norbixin chronic oral administration for 6 months in Abca4^-/- Rdh8^-/- mice following the “early curative” supplementation showed optimal neuroprotection and maintenance of photoreceptor function and reduced ocular A2E accumulation. Thus, norbixin appears promising as a systemic drug candidate for both AMD and STGD treatment.

  

  Effect of norbixin on ERG and retinal phototoxicity after BLD in BALB/c mice. (A) schematic representation of the protocol design. (B) Scotopic A wave, (C) Scotopic B wave, (D) Photopic B wave, ERG recorded 7 days after BLD. (E) Representative cryosection pictures showing Hoechst 33342 staining of the retinal cell nuclei one week after BLD. (F) Graph showing the number of photoreceptor layers measured along the retina each 200 μm from the optic nerve. (G) Histograms showing the area under the curve (AUC) calculated from the photoreceptor layer quantification and used to perform statistical analyses. IP: intra-peritoneal; no BLD: no blue light damage; no inj.: no injection; OS: outer segment; ONL: outer nuclear layer; INL: inner nuclear layer; GCL: ganglion cell layer. Bars represent mean ± s.e.m. with n = 8 per group. ^# or *p<0.05, ^## or **p<0.01, ^### or ***p<0.001, ^#### or ****p<0.0001 compared to non-injected or to vehicle, respectively (One-way ANOVA, Dunnett's post-test).

  
  
  

  

  Kinetics of loss of amplitude of scotopic A and B waves and photopic B wave, of A2E accumulation and of loss of photoreceptor nuclear layers in Abca4^-/- Rdh8^-/- mice aged between 2 and 18 months. (A) Scotopic A wave recorded at a flash intensity of 10 cd.s/m² (n = 30-50). (B) Scotopic B wave recorded at a flash intensity of 10 cd.s/m² (n = 30-50). (C) Photopic B wave recorded at a flash intensity of 30 cd.s/m² (n = 30-50). (D) Kinetics of loss of photoreceptor nuclear layers (n = 7-14). (E) Kinetics of A2E accumulation (n = 15-40). Bars represent mean ± s.e.m. *p<0.05, **p<0.01, ***p<0.001, ***p<0.0001 (One-way ANOVA, Dunnett's post-test).

  
  
  

  

  RPE65, cathepsin D and GFAP immunostaining in Abca4^-/- Rdh8^-/- mice of different ages. Pictures showing retinal cryosections of 2-month-old (A, C, E) and 18-month-old (B, D, F) mice captured in bright field (left pictures) or after immunostaining for cathepsin D (A, B), RPE65 (C, D) and GFAP (E, F). OS: outer segment; ONL: outer nuclear layer; INL: inner nuclear layer; GCL: ganglion cell layer.

  
  
  

  

  Effect of norbixin preventive supplementation from 1.5 to 7.5 months in Abca4^-/- Rdh8^-/- mice. (A) schematic representation of the 6-month preventive supplementation protocol design. (B) Scotopic A wave, (C) Scotopic B wave, (D) Photopic B wave, recorded after 6 months of oral supplementation with norbixin in Abca4^-/- Rdh8^-/- mice compared to mice fed with normal chow (vehicle) and to 1.5-month-old mice. (E) Quantification of photoreceptor nuclear layers along the superior and inferior poles of the retina each measured every 200 μm apart from the optic nerve. (F) A2E quantification in eyes from 1.5-month-old Abca4^-/- Rdh8^-/- mice, 7.5-month-old mice fed with normal chow or with norbixin-containing pellets. Bars represent mean ± s.e.m. with n= 8 mice per group (i.e. n=16 eyes per group for ERG). **p<0.01 compared to vehicle (One-way ANOVA, Dunnett's post-test).

  
  
  

  

  Effect of norbixin early curative supplementation from 9 to 15 months in Abca4^-/- Rdh8^-/- mice. (A) Schematic representation of the 6-month early curative supplementation protocol design. (B) Scotopic A wave, (C) Scotopic B wave, (D) Photopic B wave ERG recorded after 6 months of oral supplementation with norbixin in Abca4^-/-Rdh8^-/- mice compared to mice fed with normal chow (vehicle) and to 1.5 and 9-month-old mice. (E) Quantification of photoreceptor nuclear layers along the superior and inferior poles of the retina each measured every 200 μm apart from the optic nerve. (F) A2E quantification in eyes from 9-month-old Abca4^-/- Rdh8^-/- mice, 15-month-old mice fed with normal chow or with norbixin-containing pellets. Bars represent mean ± s.e.m. with n = 6 per group (i.e. n=12 eyes for the norbixin treated group and n=11 eyes for the vehicle treated group for ERG). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 compared to vehicle (One-way ANOVA, Dunnett's post-test).

  
  
  

  

  Effect of norbixin late curative supplementation from 12 to 17 months in Abca4^-/- Rdh8^-/- mice. (A) Schematic representation of the 5-month late curative supplementation protocol design. (B) Scotopic A wave ERG recorded after 5 months of oral supplementation with norbixin in Abca4^-/- Rdh8^-/- mice compared to mice fed with normal chow (vehicle) and to 1.5- and 12-month-old mice. (C) Scotopic B wave. (D) Photopic B wave. (E) Quantification of photoreceptor nuclear layers along the superior and inferior poles of the retina each measured every 200 μm apart from the optic nerve. (F) A2E quantification in eyes from 12-month-old Abca4^-/- Rdh8^-/- mice, 17-month-old mice fed with normal chow or with norbixin-containing pellets. (G) Representative images of lipofuscin content in RPE cells of 17-month-old vehicle and norbixin-treated mice. Large granules of lipofuscin are found in the RPE cytoplasm (white asterisk). (H) Histograms showing the quantified lipofuscin granules expressed by area of 100 μm². (I) Histograms representing the surface of cytoplasm occupied by lipofuscin and expressed in percentage of total cytoplasm surface. Bars represent mean ± s.e.m. with n = 8 per group (i.e. n=16 eyes per group for ERG). *p<0.05, **p<0.01 compared to vehicle (One-way ANOVA, Dunnett's post-test).