Nrf2 activation by TUDCA in experimental models of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a progressive neurological disorder, mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the cause of PD remains elusive, several lines of evidence implicate mitochondrial dysfunction and oxidative stress as possible mechanisms by which cell death occurs in this disease. Under oxidative stress, the master regulator of cellular redox status, nuclear factor erythroid 2 related factor 2 (Nrf2), is responsible for activating the transcription of several cytoprotective enzymes, namely glutathione peroxidase 1 (Gpx1), heme oxygenase-1 (HO-1) and superoxide dismutase 2 (SOD2), being a promising target to limit reactive oxygen species (ROS)-mediated damage in PD. In this work, we aim to evaluate the ability of tauroursodeoxycholic acid (TUDCA) to modulate, not only the Nrf2 pathway and the expression of the Nrf2 stabilizer, DJ-1, but also the cellular redox status, in both animal and cellular models of PD, using twelve-week-old C57BL/6 male mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the human neuroblastoma cell line, SH-SY5Y, treated with 1-methyl-4-phenylpyridinium (MPP+). Our Western blot results, together with quantitative real time polymerase chain reaction, demonstrate that TUDCA treatment increases DJ-1, Nrf2, Gpx1, HO-1 and SOD2 expression, in mice striatum and midbrain. Moreover, enzymatic assays also reveal that TUDCA treatment enhances Gpx biological activity, in mice. In SH-SY5Y cells, we demonstrate by immunocytochemistry that TUDCA induces Nrf2 nuclear translocation, with the consequent increase in HO-1 mRNA levels. Additionally, TUDCA also attenuates both MPP+-induced ROS production and lipid peroxidation, in this cell line. Together, our results suggest that TUDCA is a promising agent to limit ROS-mediated damage, in different models of PD acting, at least in part, through modulation of the Nrf2 signaling pathway, and therefore, should be considered a promising therapeutic agent to be implemented in PD.