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Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease.
Mol Neurobiol. 2012 Oct; 46(2):475-86.MN

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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Castro-Caldas M
Research Institute for Medicines and Pharmaceutical Sciences, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Carvalho AN
No affiliation info available
Rodrigues E
No affiliation info available
Henderson CJ
No affiliation info available
Wolf CR
No affiliation info available
Rodrigues CM
No affiliation info available
Gama MJ
No affiliation info available

MeSH

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineAnimalsCell DeathDisease Models, AnimalDopaminergic NeuronsHSP27 Heat-Shock ProteinsI-kappa B ProteinsIntracellular SpaceJNK Mitogen-Activated Protein KinasesMiceMice, Inbred C57BLMice, KnockoutNF-KappaB Inhibitor alphaNF-kappa BNerve DegenerationNeuroprotective AgentsParkinson DiseasePhosphorylationReactive Oxygen SpeciesTaurochenodeoxycholic Acidbcl-Associated Death Protein

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22773138

Clinical Trial Links

Trial of Ursodeoxycholic Acid (UDCA) for Parkinson's Disease: The "UP" Study

Citation

Castro-Caldas, M, et al. "Tauroursodeoxycholic Acid Prevents MPTP-induced Dopaminergic Cell Death in a Mouse Model of Parkinson's Disease." Molecular Neurobiology, vol. 46, no. 2, 2012, pp. 475-86.
Castro-Caldas M, Carvalho AN, Rodrigues E, et al. Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease. Mol Neurobiol. 2012;46(2):475-86.
Castro-Caldas, M., Carvalho, A. N., Rodrigues, E., Henderson, C. J., Wolf, C. R., Rodrigues, C. M., & Gama, M. J. (2012). Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease. Molecular Neurobiology, 46(2), 475-86. https://doi.org/10.1007/s12035-012-8295-4
Castro-Caldas M, et al. Tauroursodeoxycholic Acid Prevents MPTP-induced Dopaminergic Cell Death in a Mouse Model of Parkinson's Disease. Mol Neurobiol. 2012;46(2):475-86. PubMed PMID: 22773138.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease. AU - Castro-Caldas,M, AU - Carvalho,A Neves, AU - Rodrigues,E, AU - Henderson,C J, AU - Wolf,C R, AU - Rodrigues,C M P, AU - Gama,M J, Y1 - 2012/07/08/ PY - 2012/05/02/received PY - 2012/06/21/accepted PY - 2012/7/10/entrez PY - 2012/7/10/pubmed PY - 2013/2/28/medline SP - 475 EP - 86 JF - Molecular neurobiology JO - Mol Neurobiol VL - 46 IS - 2 N2 - 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. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/22773138/Tauroursodeoxycholic_acid_prevents_MPTP_induced_dopaminergic_cell_death_in_a_mouse_model_of_Parkinson's_disease_ L2 - https://dx.doi.org/10.1007/s12035-012-8295-4 DB - PRIME DP - Unbound Medicine ER -