title: Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease.
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.
authors: Research Institute for Medicines and Pharmaceutical Sciences, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: M
authors: M
authors: Castro-Caldas
authors: A Neves
authors: AN
authors: Carvalho
authors: E
authors: E
authors: Rodrigues
authors: C J
authors: CJ
authors: Henderson
authors: C R
authors: CR
authors: Wolf
authors: C M P
authors: CM
authors: Rodrigues
authors: M J
authors: MJ
authors: Gama
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; C000606205:Nfkbia protein, mouse; D017382:Reactive Oxygen Species; D051025:bcl-Associated Death Protein; D000072000:NF-KappaB Inhibitor alpha; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048031:JNK Mitogen-Activated Protein Kinases