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

Abstract

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.

Long-Chain Polyunsaturated Fatty Acids and Their Metabolites Regulate Inflammation in Age-Related Macular Degeneration

“…181 Fontaine et al found that A2E promoted inflammation and angiogenesis partially via inducing the transactivation of PPARs and retinoid X receptors (RXR) in RPE cells. 185,186 PPARγ coactivator (PGC)-1α is a protein that increases RPE metabolism, maintains mitochondrial homeostasis, and protects against ROS damage. 187 Zhang et al found that PGC-1α −/− mice on a high-fat diet were more prone to developing AMD.…”

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)

“…Norbixin modulates inflammation, as demonstrated by its inhibitory effect on A2E-induced expression of IL-6 and IL-8 and by its effect on the transactivation of NF-κB and AP-1. In addition, our previous observations demonstrated that norbixin impairs VEGF expression induced by A2E [ 5 ]. Norbixin also reduces the accumulation of A2E by primary porcine RPE cells in vitro [ 4 ].…”

“…Oral complementation with norbixin also reduces A2E and lipofuscin accumulation in RPE cells in these animals [ 7 ]. The beneficial effects of norbixin are potentially associated with its interaction with several nuclear receptors: PPAR-γ, PPAR-α, PPAR-β/δ, and also RXR-α [ 5 , 8 ]. We proposed that norbixin behaves as a neutral antagonist of these nuclear receptors, thus inhibiting their transactivation induced by A2E [ 5 ].…”

Resvega, a Nutraceutical Preparation, Affects NFκB Pathway and Prolongs the Anti-VEGF Effect of Bevacizumab in Undifferentiated ARPE-19 Retina Cells

“…The phosphorylation of AKT leads to the expression of inflammatory cytokines (IL-6, IL-8, IL-18), which support the inflammatory environment involved in AMD pathogenesis, and contributes to VEGF secretion by the inflammatory-induced angiogenesis process [ 34 ]. Previous study has revealed that RGA, as an anti-inflammatory formulation, could modulate the expression of inflammatory cytokines such as IL-6 and IL-8 [ 20 ].…”