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Exp Neurol. 2017 Sep;295:77-87. doi: 10.1016/j.expneurol.2017.05.009. Epub 2017 May 25.

Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease.

Author information

1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
2
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
3
Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany; Chronic Disease Research Center (CEDOC), NOVA Medical School, Campo dos Mártires da Pátria, 130, 1169-056 Lisbon, Portugal; Max Planck Institute for Experimental Medicine, Göttingen, Germany.
4
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal; Department of Life Sciences, Faculty of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal. Electronic address: mcastrocaldas@ff.ulisboa.pt.

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, mitochondrial dysfunction and severe oxidative stress are strongly implicated in the cell death that characterizes the 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 (GPx) and heme oxygenase-1 (HO-1). Nrf2 is a promising target to limit reactive oxygen species (ROS)-mediated damage in PD. Here, we show that tauroursodeoxycholic acid (TUDCA) prevents both 1-methyl-4-phenylpyridinium (MPP+)- and α-synuclein-induced oxidative stress, through Nrf2 activation, in SH-SY5Y cells. Additionally, we used C57BL/6 male mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to elucidate the effect of TUDCA in this in vivo model of PD. In vivo, TUDCA treatment increases the expression of Nrf2, Nrf2 stabilizer DJ-1, and Nrf2 downstream target antioxidant enzymes HO-1 and GPx. Moreover, we found that TUDCA enhances GPx activity in the brain. Altogether, 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. Therefore, TUDCA should be considered a promising therapeutic agent to be implemented in PD.

KEYWORDS:

MPTP/MPP+; Nrf2; Oxidative stress; Redox balance; TUDCA; α-Synuclein

PMID:
28552716
DOI:
10.1016/j.expneurol.2017.05.009
[Indexed for MEDLINE]

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