Chemical stress induces up-regulation of Nurr1: role of antioxidants

Chemical stress induces up-regulation of Nurr1: role of antioxidants Laura Bordoni1, Donatella Fedeli2, Cinzia Nasuti2, Dennis Fiorini3, Luana Quassinti2, Massimo Bramucci2 and Rosita Gabbianelli1 1 School of Advanced Studied, 2School of Pharmacy and 3School of Science and Technology, University of Camerino, Italy Objectives The nuclear receptor NR4A2 (Nurr1) has been demonstrated to be able to modulate cellular homeostasis, energy metabolism, inflammatory response and dopaminergic system. Nurr1 is induced by stress and injury in brain, and it is necessary for maintenance of midbrain dopaminergic neurons because it regulates the dopaminergic synthesis. Down-regulation of Nurr1 has been observed together with a reduced expression of tyrosine hydroxylase (TH) and an increased level of -synuclein in Parkinson’s disease. Finally, a key role in the protection against oxidative and inflammatory stress associated to neurodegeneration has been associated to Nurr1. The aim of this study was to determine the role of antioxidants in modulating the up-regulation of Nurr1 due to chemical stressor residues in food. Methods PC12 dopaminergic cell line has been incubated with the lipophilic chemical stressor permethrin (Perm) in corn oil, for 72h with various antioxidants or antioxidants vehicles, like glutathione (GSH), tocotrienols, Extra Virgin Olive oil (EVO) and Electrolyzed Reduced Water (ERW). qPCR of Nurr1 was used to screen the protective effect of the analyzed antioxidants. Corn oil and EVO were analyzed as vehicle for their impact on Nurr1, Nrf2 and NFkB gene expression. Western Blotting analysis of Nurr1 and TH was performed as confirm where data showed interesting evidences. Trypan blue was used to count cells and determine cell viability. Results Cell viability, reduced in dopaminergic cell line exposed to Perm as chemical stressor, resulted to be improved only by EVO due to its redox and anti-inflammatory capacity, in agreement with its ability to promote Nrf2 and to inhibit NF-kB gene expression; moreover, the two oils, EVO and corn oil, modulated Nurr1 and TH similarly. GSH, tocotrienols and ERW could reduce the up-regulation of Nurr1 due to chemical stress, although ERW was more efficient. Conclusion EVO inhibits NF-kB and protects PC12 improving cell viability reduced by Perm. ERW was able to counterbalance the up-regulation of Nurr1 and TH, thus they could be helpful as a dietary tool in the prevention of stressor-induced-dopaminergic neurodegeneration.