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Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease

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Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease. / Castro-Caldas, M.; Carvalho, A. Neves; Rodrigues, E.; Henderson, C. J.; Wolf, C. R.; Rodrigues, C. M. P.; Gama, M. J.

In: Molecular Neurobiology, Vol. 46, No. 2, 2012, p. 475-486.

Research output: Contribution to journalArticle

Harvard

Castro-Caldas, M, Carvalho, AN, Rodrigues, E, Henderson, CJ, Wolf, CR, Rodrigues, CMP & Gama, MJ 2012, 'Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease' Molecular Neurobiology, vol 46, no. 2, pp. 475-486., 10.1007/s12035-012-8295-4

APA

Castro-Caldas, M., Carvalho, A. N., Rodrigues, E., Henderson, C. J., Wolf, C. R., Rodrigues, C. M. P., & Gama, M. J. (2012). Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease. Molecular Neurobiology, 46(2), 475-486. 10.1007/s12035-012-8295-4

Vancouver

Castro-Caldas M, Carvalho AN, Rodrigues E, Henderson CJ, Wolf CR, Rodrigues CMP et al. Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease. Molecular Neurobiology. 2012;46(2):475-486. Available from: 10.1007/s12035-012-8295-4

Author

Castro-Caldas, M.; Carvalho, A. Neves; Rodrigues, E.; Henderson, C. J.; Wolf, C. R.; Rodrigues, C. M. P.; Gama, M. J. / Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease.

In: Molecular Neurobiology, Vol. 46, No. 2, 2012, p. 475-486.

Research output: Contribution to journalArticle

Bibtex - Download

@article{11bd02fc47344fd482d351eb3136c841,
title = "Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease",
author = "M. Castro-Caldas and Carvalho, {A. Neves} and E. Rodrigues and Henderson, {C. J.} and Wolf, {C. R.} and Rodrigues, {C. M. P.} and Gama, {M. J.}",
year = "2012",
doi = "10.1007/s12035-012-8295-4",
volume = "46",
number = "2",
pages = "475--486",
journal = "Molecular Neurobiology",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease

A1 - Castro-Caldas,M.

A1 - Carvalho,A. Neves

A1 - Rodrigues,E.

A1 - Henderson,C. J.

A1 - Wolf,C. R.

A1 - Rodrigues,C. M. P.

A1 - Gama,M. J.

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.

PY - 2012

Y1 - 2012

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-?B 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.

AB - 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-?B 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.

U2 - 10.1007/s12035-012-8295-4

DO - 10.1007/s12035-012-8295-4

M1 - Article

JO - Molecular Neurobiology

JF - Molecular Neurobiology

IS - 2

VL - 46

SP - 475

EP - 486

ER -

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