Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease
| Autor: | Elsa Rodrigues, Cecília M. P. Rodrigues, Sara Moreira, Maria João Nunes, Margarida Castro-Caldas, Maria João Gama, Andreia Neves Carvalho, Tiago F. Outeiro, Luísa Lemos, Alexandra Isabel Rosa, Inês T.E. Fonseca |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Parkinson's disease NF-E2-Related Factor 2 Substantia nigra Pharmacology medicine.disease_cause Cell Line Taurochenodeoxycholic Acid Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Developmental Neuroscience medicine Animals Parkinson Disease Secondary RNA Small Interfering chemistry.chemical_classification Glutathione Peroxidase Reactive oxygen species Cell Death Pars compacta MPTP Glutathione peroxidase Brain MPTP Poisoning Tauroursodeoxycholic acid medicine.disease Mice Inbred C57BL Oxidative Stress 030104 developmental biology Neurology Biochemistry chemistry alpha-Synuclein Lipid Peroxidation Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Experimental Neurology. 295:77-87 |
| ISSN: | 0014-4886 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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