Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3 beta in MPP+-Induced Cell Damage

WOS: 000464958400014PubMed ID: 30965670Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3 beta (GSK-3 beta) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP+-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPAR gamma) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3 beta enzyme inhibition against MPP+. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3 beta enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3 beta along with PPAR gamma activation may be responsible for neuroprotection.Scientific and Technology Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [215S528]; Ege University Scientific Research FoundationEge University [15/ECZ/012, 2016/BIL/004]This research was funded by The Scientific and Technology Research Council of Turkey (TUBITAK) (215S528) and Ege University Scientific Research Foundation (15/ECZ/012, 2016/BIL/004)