Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson’s Disease

Abstract

Parkinson's disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

“…In humans, defective protein folding is thought to be connected with many neurodegenerative diseases [12,122]. In this respect, TUDCA not only has been shown to inhibit apoptosis induced by several stimuli in neuronal cells in vitro, but also to play a cytoprotective role in animal models of neurological disorders, such as Alzheimer's disease (AD) [6,35,[123][124][125], Parkinson's disease (PD) [3,6,[126][127][128][129][130], Huntington's disease (HD) [24,131], amyloid latheral sclerosis (ALS) [132][133][134], and Prion diseases [135]. Furthermore, pretreatment with TUDCA significantly reduced glutamate-induced apoptosis of rat cortical neurons [38] and improved synaptic plasticity as well as cognitive and motor impairment in the hippocampus of microcystin-leucine-arginine-treated rats [136,137].…”

“…The second most common neurodegenerative disorder worldwide is Parkinson's disease [127]. PD is characterized by the loss of dopaminergic neurons in the substantia nigra of the brain, which results in severe motor symptoms such as dyskinesia, tremor, and speech impairment [3,[127][128][129][130]. Dopamine cell death in PD may result from either genetic or environmental factors.…”

“…Other reports suggested that TUDCA prevented oxidative stress mainly via enhanced expression of Nrf2, DJ-1, and antioxidant enzymes heme oxygenase-1 (HO-1) and glutathione peroxidase (GPx) [128]. The latest studies show that the MPTP model of PD TUDCA restored ATP levels, prevented mitochondrial dysfunction, alleviated neuroinflammation, and significantly improved motor symptoms [130]. Currently, a novel approach towards the utilization of bile acids in PD is being considered.…”

Drug Repurposing in Parkinson’s Disease

“…A phase 1, open-label trial evaluating the safety and pharmacokinetics of 50mg/kg/day UDCA in 20 patients with PD is currently underway (NCT02967250) while a trial of UDCA in PD patients to evaluate the effect of on disease progression has received funding and is due to start imminently. PD-specific pharmacokinetic data regarding UDCA is awaited though in view of the potential issues regarding incomplete absorption of UDCA from the gut, interest is growing in the UDCA derivative tauro-ursodeoxycholic acid (TUDCA) (not currently approved for use), which has demonstrated better orally bioavailability, crosses the blood-brain barrier and has demonstrated neuroprotection against MPTP-and α-synuclein-induced stress in vitro and in vivo [72,[77][78][79] and indicated potential benefits in a small RCT in 34 patients with ALS [80] and may offer better potential.…”

The evaluation of 2.3-diazepine influence on tissue respiration of the liver and its exocrine function in rats with a rotenone model of Parkinson’s disease

“…Recently, Rosa A, et al have shown in mice that some BAs, in particular tauroursodeoxycholic acid, act as mitochondrial sta-bilizer and anti-apoptotic agent in a number of models of neurodegenerative diseases, including PD. This substance prevented a decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation [23].…”