A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cells in vitro

Abstract

N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing apoptosis, angiogenesis and inflammation. It has been proposed that A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-a. Here we show that A2E binds and transactivates not only RARs, but also peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs). Norbixin, which protects retinal pigment epithelium (RPE) cells against apoptosis induced by combined blue light illumination and A2E exposure, is also a ligand of these nuclear receptors (NRs) but does not induce their transactivation. Norbixin inhibits RXRs andPPARs but enhances RARs transactivation induced by A2E. Norbixin also inhibits PPAR-g transactivation induced by its high affinity ligand troglitazone. activator protein 1 (AP-1) transactivation, and the mRNA expression of the inflammatory interleukins (IL) 6 and 8 and of vascular endothelial growth factor (VEGF) that are enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression but has neither effect on extracellular signal-regulated kinase (ERK) phosphorylation, nor on IL-18 mRNA Norbixin modulates NRs activation by A2E in RPE cells 2 expression in response to A2E. Altogether, we show for the first time that A2E deleterious biological effects appear to be mediated through RARs, PPARs and RXRs. Moreover, we report that the modulation of these NRs by norbixin may open new avenues for the treatment of AMD. Photoprotection of RPE cells by norbixin correlates with maintained levels of the antiapoptotic B-cell lymphoma 2 (Bcl2) protein. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-kB and

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

“…Dilda, J.-A. Sahel, S. Veillet, R. Lafont, S. Camelo, manuscript posted on bioRxiv) [ 98 ]. These in vitro data confirm the anti-inflammatory effects of norbixin observed in human studies in vivo [ 99 , 100 ].…”

“…However, drug development using norbixin and apocarotenoids in general, as active principles, requires a better understanding of their exact mode of action. We recently started to explore the molecular clues explaining the antioxidant and anti-inflammatory properties of norbixin and found out that it modulates very precisely the activity of certain nuclear receptors [ 98 , 101 ]. Due to the pleiotropic effects of nuclear receptors that have been implicated in AMD [ 103 ], this observation supports the broad beneficial effects of norbixin.…”