Anti-Inflammatory Effects and Photo- and Neuro-Protective Properties of BIO203, a New Amide Conjugate of Norbixin, in Development for the Treatment of Age-Related Macular Degeneration (AMD)

Abstract

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.

RAR Inhibitors Display Photo-Protective and Anti-Inflammatory Effects in A2E Stimulated RPE Cells In Vitro through Non-Specific Modulation of PPAR or RXR Transactivation

“…Previous observations and our present results, summarized in Table 1 , confirmed the importance of PPAR and/or RXR transactivation by A2E in the induction of inflammation [ 23 , 27 ]. In addition, PPAR and/or RXR modulation was also involved in VEGF expression and in the survival of RPE cells against blue light challenge in the presence of A2E, perhaps through a reduction in AKT phosphorylation [ 23 ].…”

“…This hypothesis was apparently further confirmed by the fact that the RAR-α antagonist BMS 195614 reduced the RAR transactivation induced by A2E by 147.8% ( p < 0.001) ( Figure 5 A). However, we previously published that norbixin protects the primary porcine RPE cells against A2E-mediated phototoxicity and limits VEGF and inflammatory cytokines mRNA expression, and this was associated with the inhibition of the transactivation of PPAR and RXR induced by A2E [ 23 , 26 , 27 ]. To confirm the role of RAR in A2E’s biological effects, we tested the effect of norbixin on the RAR transactivation induced by A2E.…”

“…An important role for the α-isoform of the RAR in A2E induced VEGF expression and cytotoxic effects has been reported [ 14 , 15 ]. However, our own previous studies suggested that instead of RAR, it was PPAR and RXR transactivations that were implicated in A2E-induced inflammation and angiogenesis [ 23 , 27 ]. Here, using our established model of primary porcine RPE cells, we re-evaluated the roles of RAR, PPAR and RXR in A2E’s mechanisms of action.…”

A systematic literature review on the pharmacological applications of the carotenoid norbixin

“…Both compounds share a similar mechanism of action involving inhibition of PPARs, reduced transactivation of nuclear factor kappa B and activator protein (AP-1), and reduced expression of A2E-induced interleukins (IL-6 and IL-8) and vascular endothelial growth factor, processes directly involved in inflammation and angiogenesis critical for AMD. According to the authors, the new biomaterial and norbixin could be candidates for effective drugs for the treatment of AMD (Fontaine et al, 2023). In the latest work, it was demonstrated by the authors that photoprotection and the anti-angiogenic and anti-inflammatory effects of norbixin are not related to the inhibition of RAR transactivation, but rather with the inhibition of PPAR and RXR transactivation (Fontaine et al, 2024).…”

Classification Maps: A New Mathematical Tool Supporting the Diagnosis of Age-Related Macular Degeneration

“…Recently, many articles on the etiology, pathophysiology or treatment of the exudative form of AMD have been published [19][20][21][22]. For example, Tadao Maeda et al discussed trends of stem cell therapies in AMD [23].…”