Parkinson's disease
The effects of bile acids on chemical and genetic models of Parkinson's disease (PD), which is characterized by the selective loss of dopaminergic neurons in the substantia nigra region of the brain and a resulting tremor, have been reported. Sodium nitroprusside (SNP)-induced cytotoxicity of human dopaminergic SH-SY5Y cells has been used as a model of PD. UDCA was found to dose-dependently (50–200 μM) decrease SNP-related cell death. UDCA reduced reactive oxygen species (ROS), reactive nitrogen species (peroxynitrite and nitric oxide), and helped to maintain intracellular glutathione (GSH) levels. Apoptosis markers including nuclear fragmentation, caspase activation, and cytochrome c release were correspondingly reduced. Inhibiting phosphatidylinositiol-3-kinase (PI3K) and Akt/PKB blocked the favorable effects of UDCA on SNP-induced cytotoxic cell death (Chun and Low, 2012).
Bile acids have also been implicated in PD through genetic association studies. In a meta-analysis of genome-wide association study (GWAS) data based on the genotypes of 2,525,705 SNPs in 4238 PD cases and 4239 non-PD controls, a total of 3 SNPs were found to be statistically associated with PD, including a non-synonymous missense variant in HSD3B7 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7) (Song and Lee, 2013). Recessive mutations in HSD3B7, which catalyzes the second step in the classical pathway of bile acid synthesis, are associated with loss of bile acid synthetic capability and progressive liver disease (Cheng et al., 2003). In a GWAS of 48,844 SNPs residing in miRNA-binding site variants, 32 SNPs were associated with PD that were located in the 3′ untranslated regions of 13 genes including HSD3B7 (Ghanbari et al., 2016), providing further genetic evidence for a role of bile acids in PD.
Mitochondrial dysfunction has been associated with PD (Luo et al., 2015). To identify compounds that could restore mitochondrial function in skin fibroblasts obtained from patients with a PD parkin (PARK2) gene mutation, a 2000 compound library was screened for significant improvement in mitochondrial membrane potential (Mortiboys et al., 2013). Ursocholanic acid and the related compound dehydro(11,12)ursolic acid lactone were among the top 15 compounds that had dose response characteristics favorable for drug development and lacked many of the disadvantages of the other top hits. The structurally related bile acid UDCA was also found to rescue mitochondrial function to a similar extent, which was dependent upon activation of the glucocorticoid receptor and increased phosphorylation of Akt. UDCA was also found to restore mitochondrial function in fibroblasts obtained from a PD patient with a LRRK2-G2019S mutation.
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin is a widely used toxin model for PD, replicating most of the clinical and pathological features of PD in humans and animal models. TUDCA was found to play a role in ameliorating neurodegeneration in MPTP-induced degeneration of dopaminergic neurons in the nigrostriatal axis in C57BL/6 glutathione S-transferase pi (GSTP) null mice (Castro-Caldas et al., 2012). Treatment of mice with TUDCA prior to MPTP caused a 30% reduction in loss of dopaminergic neurons and reduced dopaminergic fiber loss. MPTP toxicity has also been associated with increased ROS production and activation of JNK-mediated apoptosis (Huang et al., 2016). TUDCA reduced levels of ROS and preserved levels of phosphorylated JNK (p-JNK) (Castro-Caldas et al., 2012).