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

Abstract

Atrophic 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.

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

“…Moreover, we suggest that the di-apocarotenoid, norbixin, regulates A2E biological activity by antagonizing partially PPAR and RXR. These partial inhibitory capacities seem correlated with the anti-inflammatory effects of norbixin in vitro and also potentially explain our previous published results showing that norbixin is protective in various in vivo animal models of AMD [ 23 , 24 ]. More broadly modulation of NRs by carotenoids such as lutein/zeaxanthin or β-carotene may explain their reported beneficial effects in AMD patients by modulating A2E’s effects [ 48 , 49 ].…”

“…Exploration of the role of PPARs and RXRs in carotenoid protective effects may help improve their clinical efficacy. Here we tested the effects of norbixin a di-apocarotenoid that protects primary porcine RPE cells against A2E and blue-light exposure in vitro and is protective in various in vivo animal models of AMD [ 23 , 24 ]. In agreement with a previous study showing that norbixin reduced NF-κB and IL-6 expression in vivo [ 25 ], here we demonstrated the modulatory effects of norbixin on A2E-induced expression of IL-6, IL-8, MMP9, CCL2 and VEGF, as well as on the transactivation of NF-κB and of AP-1, and on the phosphorylation of AKT ( Figure 8 ).…”

“…We have previously demonstrated that norbixin protects primary porcine RPE cells from phototoxicity induced by blue-light illumination coupled with A2E-exposure in vitro [ 23 ]. Moreover, norbixin reduces accumulation of A2E in RPE cells in vitro [ 23 ] and ocular accumulation of A2E in vivo [ 24 ]. Recently, it has been reported that norbixin is a PPAR-γ ligand with agonist activity [ 25 ].…”

Beyond AREDS Formulations, What Is Next for Intermediate Age-Related Macular Degeneration (iAMD) Treatment? Potential Benefits of Antioxidant and Anti-inflammatory Apocarotenoids as Neuroprotectors

“…A2E accumulation is observed during the early stages of AMD. Accordingly, long-term in vivo administration of norbixin reduces the ocular accumulation of A2E in ABCA4 −/− and Rdh8 −/− mice [ 97 ], suggesting that norbixin could slowdown the subretinal accumulation of A2E that is observed during iAMD. It was further demonstrated in vitro that norbixin significantly reduced the production of VEGF and of several inflammatory cytokines, such as IL-6 and IL-8, in porcine RPE cells cultivated in the presence of A2E (V. Fontaine, M. Fournié, E. Monteiro, T. Boumedine, C. Balducci, L. Guibout, M. Latil, PJ.…”

In vivo evaluation of bone repair guided with biological membrane based on polyhydroxybutyrate and norbixin

“…This pigment is known to have antioxidant and antitumor properties that can support the bone repair process with a protective effect on tissue data, with potential limitation to oxidative stress and consequent abbreviation of the inflammatory process. 22,23 Due to its antimicrobial effects, 24 it can act as a barrier against the invasion of microorganisms and protect the injury site from possible infections, facilitating the natural healing process. Widely used in the food industry (natural nontoxic dye) and textiles (fabric dyeing), the norbixin content found naturally in annatto is low.…”