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Tauroursodeoxycholic Acid Prevents MPTP-Induced Dopaminergic Cell Death in a Mouse Model of Parkinson’s Disease

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Abstract

Mitochondrial dysfunction and oxidative stress are implicated in the neurodegenerative process in Parkinson’s disease (PD). Moreover, c-Jun N-terminal kinase (JNK) plays an important role in dopaminergic neuronal death in substantia nigra pars compacta. Tauroursodeoxycholic acid (TUDCA) acts as a mitochondrial stabilizer and anti-apoptotic agent in several models of neurodegenerative diseases. Here, we investigated the role of TUDCA in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in a mouse model of PD. We evaluated whether TUDCA modulates MPTP-induced degeneration of dopaminergic neurons in the nigrostriatal axis, and if that can be explained by regulation of JNK phosphorylation, reactive oxygen species (ROS) production, glutathione S-transferase (GST) catalytic activation, and Akt signaling, using C57BL/6 glutathione S-transferase pi (GSTP) null mice. TUDCA efficiently protected against MPTP-induced dopaminergic degeneration. We have previously demonstrated that exacerbated JNK activation in GSTP null mice resulted in increased susceptibility to MPTP neurotoxicity. Interestingly, pre-treatment with TUDCA prevented MPTP-induced JNK phosphorylation in mouse midbrain and striatum. Moreover, the anti-oxidative role of TUDCA was demonstrated in vivo by impairment of ROS production in the presence of MPTP. Finally, results herein suggest that the survival pathway activated by TUDCA involves Akt signaling, including downstream Bad phosphorylation and NF-κB activation. We conclude that TUDCA is neuroprotective in an in vivo model of PD, acting mainly by modulation of JNK activity and cellular redox thresholds, together with activation of the Akt pro-survival pathway. These results open new perspectives for the pharmacological use of TUDCA, as a modulator of neurodegeneration in PD.

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Acknowledgments

Supported by Fundação para a Ciência e a Tecnologia (FCT) and FEDER through grants PPCDT/SAU-FCF/58171/2004 and PEst-OE/SAU/UI4013/2011, and Ph.D. fellowship SFRH/BD/39897/2007 (to ANC).

Statement of Conflicts of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal

    M. Castro-Caldas, A. Neves Carvalho, E. Rodrigues, C. M. P. Rodrigues & M. J. Gama

  2. Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal

    M. Castro-Caldas

  3. Centre of Ophthalmology, Institute of Biomedical Research in Light and Image—IBILI, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal

    A. Neves Carvalho

  4. Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    E. Rodrigues, C. M. P. Rodrigues & M. J. Gama

  5. Division of Cancer Research, Medical Research Institute, Ninewells Hospital and Medical School, Level 9, Jacqui Wood Cancer Centre, Dundee, DD1 9SY, Scotland, UK

    C. J. Henderson & C. R. Wolf

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  1. M. Castro-Caldas
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  2. A. Neves Carvalho
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  3. E. Rodrigues
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  4. C. J. Henderson
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  5. C. R. Wolf
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  6. C. M. P. Rodrigues
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  7. M. J. Gama
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Correspondence to M. J. Gama.

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M. Castro-Caldas and A. Neves Carvalho are joint first authors.

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Castro-Caldas, M., Carvalho, A.N., Rodrigues, E. et al. Tauroursodeoxycholic Acid Prevents MPTP-Induced Dopaminergic Cell Death in a Mouse Model of Parkinson’s Disease. Mol Neurobiol 46, 475–486 (2012). https://doi.org/10.1007/s12035-012-8295-4

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