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

Sara Moreira, Inês Fonseca, Maria João Nunes, Alexandra I Rosa, Luísa Lemos, Elsa Rodrigues, Andreia Neves Carvalho, Tiago F Outeiro, Cecília Maria Pereira Rodrigues, Maria João Gama, Margarida Castro-Caldas

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)77-87
Number of pages11
JournalCase reports in neurology
Volume295
DOIs
Publication statusE-pub ahead of print - Sep 2017

Keywords

  • TUDCA
  • MPTP/MPP
  • Nrf2
  • Oxidative stress
  • Redox balance
  • alpha-Synuclein

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