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1.
Int J Mol Sci ; 25(5)2024 Mar 06.
Article En | MEDLINE | ID: mdl-38474284

N-retinylidene-N-retinylethanolamine (A2E) has been associated with age-related macular degeneration (AMD) physiopathology by inducing cell death, angiogenesis and inflammation in retinal pigmented epithelial (RPE) cells. It was previously thought that the A2E effects were solely mediated via the retinoic acid receptor (RAR)-α activation. However, this conclusion was based on experiments using the RAR "specific" antagonist RO-41-5253, which was found to also be a ligand and partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. Moreover, we previously reported that inhibiting PPAR and retinoid X receptor (RXR) transactivation with norbixin also modulated inflammation and angiogenesis in RPE cells challenged in the presence of A2E. Here, using several RAR inhibitors, we deciphered the respective roles of RAR, PPAR and RXR transactivations in an in vitro model of AMD. We showed that BMS 195614 (a selective RAR-α antagonist) displayed photoprotective properties against toxic blue light exposure in the presence of A2E. BMS 195614 also significantly reduced the AP-1 transactivation and mRNA expression of the inflammatory interleukin (IL)-6 and vascular endothelial growth factor (VEGF) induced by A2E in RPE cells in vitro, suggesting a major role of RAR in these processes. Surprisingly, however, we showed that (1) Norbixin increased the RAR transactivation and (2) AGN 193109 (a high affinity pan-RAR antagonist) and BMS 493 (a pan-RAR inverse agonist), which are photoprotective against toxic blue light exposure in the presence of A2E, also inhibited PPARs transactivation and RXR transactivation, respectively. Therefore, in our in vitro model of AMD, several commercialized RAR inhibitors appear to be non-specific, and we propose that the phototoxicity and expression of IL-6 and VEGF induced by A2E in RPE cells operates through the activation of PPAR or RXR rather than by RAR transactivation.


Carotenoids , Macular Degeneration , Peroxisome Proliferator-Activated Receptors , Quinolines , para-Aminobenzoates , Anti-Inflammatory Agents , Drug Inverse Agonism , Inflammation , Macular Degeneration/metabolism , Peroxisome Proliferator-Activated Receptors/metabolism , Retinoic Acid Receptor alpha/metabolism , Retinoid X Receptors/metabolism , Retinoids/metabolism , Transcriptional Activation , Vascular Endothelial Growth Factor A/metabolism
2.
Int J Mol Sci ; 24(6)2023 Mar 10.
Article En | MEDLINE | ID: mdl-36982372

9'-cis-norbixin (norbixin/BIO201) protects RPE cells against phototoxicity induced by blue light and N-retinylidene-N-retinylethanolamine (A2E) in vitro and preserves visual functions in animal models of age-related macular degeneration (AMD) in vivo. The purpose of this study was to examine the mode of action and the in vitro and in vivo effects of BIO203, a novel norbixin amide conjugate. Compared to norbixin, BIO203 displays improved stability at all temperatures tested for up to 18 months. In vitro, BIO203 and norbixin share a similar mode of action involving the inhibition of PPARs, NF-κB, and AP-1 transactivations. The two compounds also reduce IL-6, IL-8, and VEGF expression induced by A2E. In vivo, ocular maximal concentration and BIO203 plasma exposure are increased compared to those of norbixin. Moreover, BIO203 administered systemically protects visual functions and retinal structure in albino rats subjected to blue-light illumination and in the retinal degeneration model of Abca4-/- Rdh8-/- double knock-out mice following 6 months of oral complementation. In conclusion, we report here that BIO203 and norbixin share similar modes of action and protective effects in vitro and in vivo. BIO203, with its improved pharmacokinetic and stability properties, could be developed for the treatment of retinal degenerative diseases such as AMD.


Macular Degeneration , Retinal Degeneration , Animals , Mice , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/metabolism , ATP-Binding Cassette Transporters/metabolism , Carotenoids/metabolism , Macular Degeneration/drug therapy , Macular Degeneration/metabolism , Retinal Degeneration/drug therapy , Retinal Degeneration/metabolism , Retinal Pigment Epithelium/metabolism , Retinoids/pharmacology , Rats
3.
Aging (Albany NY) ; 13(18): 22040-22058, 2021 09 20.
Article En | MEDLINE | ID: mdl-34544906

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, -ß/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.


Carotenoids/administration & dosage , Macular Degeneration/drug therapy , PPAR alpha/immunology , PPAR delta/immunology , PPAR gamma/immunology , PPAR-beta/immunology , Retinal Pigment Epithelium/drug effects , Retinoids/immunology , Angiogenesis Inhibitors/administration & dosage , Animals , Humans , Macular Degeneration/chemically induced , Macular Degeneration/genetics , Macular Degeneration/immunology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/etiology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/immunology , PPAR alpha/genetics , PPAR delta/genetics , PPAR gamma/genetics , PPAR-beta/genetics , Retinal Pigment Epithelium/immunology , Retinoid X Receptors/agonists , Retinoid X Receptors/genetics , Retinoid X Receptors/immunology , Retinoids/adverse effects , Swine , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/immunology
4.
Aging (Albany NY) ; 12(7): 6151-6171, 2020 04 07.
Article En | MEDLINE | ID: mdl-32255762

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.


Carotenoids/pharmacology , Macular Degeneration , Photoreceptor Cells, Vertebrate , Retinoids , Stargardt Disease , Animals , Drug Monitoring/methods , Electroretinography/methods , Injections, Intraperitoneal , Macular Degeneration/drug therapy , Macular Degeneration/metabolism , Macular Degeneration/prevention & control , Mice , Neuroprotective Agents/pharmacology , Photoreceptor Cells, Vertebrate/drug effects , Photoreceptor Cells, Vertebrate/metabolism , Retinoids/antagonists & inhibitors , Retinoids/metabolism , Stargardt Disease/drug therapy , Stargardt Disease/metabolism , Stargardt Disease/prevention & control , Treatment Outcome
5.
PLoS One ; 11(12): e0167793, 2016.
Article En | MEDLINE | ID: mdl-27992460

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.


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