Tauroursodeoxycholic acid (TUDCA) is neuroprotective in a chronic mouse model of Parkinson’s disease

ABSTRACT

Objective: Parkinson’s disease (PD) is a progressive motor disease of unknown etiology. Although neuroprotective ability of endogenous bile acid, tauroursodeoxycholic acid (TUDCA), shown in various diseases, including an acute model of PD,the potential therapeutic role of TUDCA in progressive models of PD that exhibit all aspects of PD has not been elucidated. In the present study, mice were assigned to one of four treatment groups: (1) Probenecid (PROB); (2) TUDCA, (3) MPTP + PROB (MPTPp); and (3) TUDCA + MPTPp. Methods: Markers for dopaminergic function, neuroinflammation, oxidative stress and autophagy were assessed using high performance liquid chromatography (HPLC), immunohistochemistry (IHC) and western blot (WB) methods. Locomotion was measured before and after treatments. Results: MPTPp decreased the expression of dopamine transporters (DAT) and tyrosine hydroxylase (TH), indicating dopaminergic damage, and induced microglial and astroglial activation as demonstrated by IHC analysis. MPTPp also decreased DA and its metabolites as demonstrated by HPLC analysis. Further, MPTPp-induced protein oxidation; increased LAMP-1 expression indicated autophagy and the promotion of alpha-synuclein (α-SYN) aggregation. Discussion: Pretreatment with TUDCA protected against dopaminergic neuronal damage, prevented the microglial and astroglial activation, as well as the DA and DOPAC reductions caused by MPTPp. TUDCA by itself did not produce any significant change, with data similar to the negative control group. Pretreatment with TUDCA prevented protein oxidation and autophagy, in addition to inhibiting α-SYN aggregation. Although TUDCA pretreatment did not significantly affect locomotion, only acute treatment effects were measured, indicating more extensive assessments may be necessary to reveal potential therapeutic effects on behavior. Together, these results suggest that autophagy may be involved in the progression of PD and that TUDCA may attenuate these effects. The efficacy of TUDCA as a novel therapy in patients with PD clearly warrants further study.

KEYWORDS:

• Parkinson’s disease
• tauroursodeoxycholic acid
• dopaminergic neurons
• dopamine transporter
• tyrosine hydroxylase
• lysosome-associated membrane protein 1 (LAMP-1)
• autophagy
• alpha synuclein
• 1-methyl-4-phenyl-1-2- 3-6-tetrahydropyridine (MPTP)

Acknowledgements

This document has been reviewed in accordance with United States Food and Drug Administration (FDA) policy and approved for publication. Approval does not signify that the contents necessarily reflect the position or opinions of the FDA nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the FDA.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Notes on contributors

Elvis Cuevas

Dr. Elvis Cuevas is a staff scientist at NCT- US Food and Drug Administration. The focal areas of Dr. Cuevas's current research at NCTR are in understanding the role gender plays in AD prevalence and the evaluation of specific neurotoxins on brain function.

Susan Burks

Susan Burks is a biologist within the division of Neurotoxicology at the National Center for Toxicological Research- US Food and Drug Administration. She provides laboratory support for neuropathology, immunohistochemistry, and in vitro models.

James Raymick

James Raymick is a Biological Science Lab Technician that has been working at National Center for Toxicological Research- US Food and Drug Administration for 10 years and previously worked at Charles Rivers Labs for 10 years.

Bonnie Robinson

Bonnie Robinson is currently a Biological Science Technician with the Division of Neurotoxicology at the National Center of Toxicology Research- National Center for Toxicological Research located in Jefferson, Arkansas. She performs HPLC to determine Dopamine and other metabolites of dopamine of the brain following exposure of neurotoxicant. She also performs analysis of the data obtained from HPLC.

Nancy P. Gómez-Crisóstomo

Nancy P. Gómez-Crisóstomo is a M.D. Ph.D., currently a research professor in Neurosciences at the Juarez Autonomous University of Tabasco, Mexico., researching the associations between metabolic syndrome and neurodegenerative diseases.

Claudia Escudero-Lourdes

Claudia Escudero-Lourdes is a PhD head of the Immunotoxicology Lab at the Chemistry Schooll /University of San Luis Potosí, México. Specialist in the molecular mechanisms involved in the toxicity and cellular metabolism of environmental contaminants, drugs/nanoparticles and food. She has contributed to the understanding of the role of inflammation-associated responses in arsenic's neurotoxicity and carcinogenicity.

Aida G. Guzman Lopez

Aida G. Guzman Lopez is a M.S. PhD and specialist in Neuropathology., currently a research professor at National Autonomous University of Mexico., researching the neuropathological changes of neurotoxins.

Srinivasulu Chigurupati

Srinivasulu Chigurupati is DVM, PhD and board-certified veterinary doctor. Dr. Chigurupati is a biologist at office of regulatory affairs, Office of Regulatory Science, Food and Drug Administration.

Joseph Hanig

Joseph Hanig is Ph. D and research pharmacologist at Office of Testing & Research, CDER/ US Food and Drug Administration.

Sherry A. Ferguson

Dr. Sherry A. Ferguson is division director of Neurotoxicology and NCTR- US Food and Drug Administration. Dr. Ferguson’s research interests are quite diverse. She began her career investigating the neurotoxicology of lead exposure in laboratory animals and that experience then carried into her postdoctoral fellowship where she studied the cognitive effects of acute drug exposure in laboratory animals. More recently, she has investigated ethnicity differences in Alzheimer’s disease.

Sumit Sarkar

Sumit Sarkar, Ph. D is a research biologist at NCTR- US Food and drug administration. Dr. Sarkar’s research work has been focused on the effects of various neurotoxicants in the brain vasculature and other components of the neurovascular unit.