Novel insights into the antioxidant role of tauroursodeoxycholic acid in experimental models of Parkinson's disease

Abstract

Impaired mitochondrial function and generation of reactive oxygen species are deeply implicated in Parkinson's disease progression. Indeed, mutations in genes that affect mitochondrial function account for most of the familial cases of the disease, and post mortem studies in sporadic PD patients brains revealed increased signs of oxidative stress. Moreover, exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor, leads to clinical symptoms similar to sporadic PD. The bile acid tauroursodeoxycholic acid (TUDCA) is an anti-apoptotic molecule shown to protect against MPTP-induced neurodegeneration in mice, but the mechanisms involved are still incompletely identified. Herein we used MPTP-treated mice, as well as primary cultures of mice cortical neurons and SH-SY5Y cells treated with MPP to investigate the modulation of mitochondrial dysfunction by TUDCA in PD models. We show that TUDCA exerts its neuroprotective role in a parkin-dependent manner. Overall, our results point to the pharmacological up-regulation of mitochondrial turnover by TUDCA as a novel neuroprotective mechanism of this molecule, and contribute to the validation of TUDCA clinical application in PD.

Postprandial Responses of Serum Bile Acids in Healthy Humans after Ingestion of Turmeric before Medium/High‐Fat Breakfasts

“…The same induction could be seen for T‐CDCA, which has been reported as a potential therapeutic agent for rheumatoid arthritis, a chronic autoimmune disease . Furthermore, the concentration of T‐UDCA, a BA which has been neuroprotective in Alzheimer's, Parkinson's, and Huntington's diseases, increased slightly when TUR was consumed prior to the MF breakfast (Table ). In contrast, the T‐DCA concentration decreased markedly with TUR consumption prior to the HF breakfast challenge; which could be of interest, as a study by Abdu et al., showed that T‐DCA was able to inhibit colon motility in mice and thus increase the risk of constipation.…”

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.…”

“…It has been discovered that TUDCA protects against MPTP-induced dopaminergic degeneration by preventing JNK phosphorylation and reducing ROS production, thus suggesting that the TUDCA-mediated survival pathway involves Akt signaling, followed by downstream phosphorylation of Bad and activation of NF-κB [27]. Accordingly, TUDCA was demonstrated to prevent 1-methyl-4-phenylpyridinium (MPP+)-induced damage in primary mouse cortical neurons [127]. Pre-incubation with TUDCA protected against MPP+-induced dysfunction of mitochondria and neuronal cell death, mainly via increased accumulation of full length PINK1 and mitochondrial localization of parkin.…”

“…TUDCA also exerted a modulatory effect on parkin phosphorylation in Ser65 position. Since PINK1-mediated phosphorylation of parkin is an important event in neuronal mitophagy, TUDCA was then suggested to exert its neuroprotective effects through the modification of PINK1/parkin-mediated mitophagy [127,146,147]. 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].…”