Bile Acid Signaling in Neurodegenerative and Neurological Disorders 2020 mdpi-res.com/d_attachment/i...
"4.2. Parkinson’s Disease
After AD, Parkinson’s disease (PD) is the second most common neurodegenerative disease marked by progressive motor deterioration. Dopaminergic neuronal death and α-synuclein-containing Lewy bodies in the substantia nigra are two known characteristics although the majority of PD cases are of sporadic origin [83]. Animal models replicate this pathology using neurotoxins, genetic mutations or combinations of the two [ 84 ]. Phenotypically, clinical diagnosis of PD is more recognizable at later stages, when motor deficits are apparent due to the misfolded α-synuclein proteins spreading to additional parts of the brain and subsequently affecting the substantia nigra. However therapeutic options starting prior to the onset of motor symptoms (prodromal phase), would be the most beneficial
in slowing the disease progression thus highlighting the importance of identifying key biomarkers for successful diagnosis [85].
PD research utilizing surgical rodent models of PD observed bile acid metabolism alterations and potential bile acid markers. Using a prodromal PD mouse model created by injecting human α-synuclein fibrils and human α-synuclein monomers (as a control) via stereotactic unilateral injection, serum and brain tissue from the mice was analyzed for metabolomics. Metabolite pathway analysis in the brain tissue of the α-synuclein fibrils treated mice yielded significant alterations of four biochemical pathways: taurine and hypotaurine metabolism, bile acid biosynthesis, glycine, serine and threonine metabolism and the citric acid cycle. The taurine and hypotaurine metabolism pathway that was disrupted includes taurine which has the crucial role in the conjugation of neuroprotective TUDCA and UDCA [ 86 ]. An adeno-associated virus-α-synuclein injected bilaterally into the substantia nigra
of rats noted that overexpression of α-synuclein, which additionally is expressed in enteric neurons, altered their gut microbiome. Along with diversifying the gut microbiome, this overexpression significantly increased the level of free bile acids and primary bile acids (CA, total MCA and β-MCA), and additionally increased secondary bile acids (taurodeoxycholic acid, taurohyodeoxycholic acid and
DCA) irrespective of influence from exercise [ 87]. Another study further clarified the presence of bile acids using a surgical mouse prodromal PD model, with three being found significantly decreased in the serum of the α-synuclein-fibrils-treated group: omega-muricholic acid, TUDCA and UDCA.
UDCA and TUDCA, both neuroprotective secondary bile acids that can pass the BBB, were markedly affected with a 17- and 14-fold decrease from the control group [ 88 ]. These surgical rodent model studies, replicating aspects of PD, shows increased research in this field will assist in therapeutic changes.
Other recent PD research has used anti-inflammatory secondary bile acids TUDCA and UDCA in experimental therapy studies. Decreased mitochondrial activity has been implicated in PD; the mitochondrial inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) replicating glial activation and the pro-inflammatory cytokine cascade of PD. A series of TUDCA injections were introduced prior to and after the MPTP-injection in a mouse model of PD. Motor capabilities improved
Int. J. Mol. Sci. 2020, 21, 5982 10 of 25 in the MPTP-treated + TUDCA groups in comparison to MPTP-treated mice along with the ability to initiate movements and amend tremors. Parkin levels, an E3 ubiquitin ligase associated with mitochondrial biogenesis, were decreased in MPTP-treated mice and were attenuated in mice treated with TUDCA prior to MPTP [ 89 ]. This same group looked into dopaminergic cell death, oxidative stress and reactive oxygen species (ROS), using the same MPTP-induced PD mouse model. SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium (MPP+) or doxycycline for two in vitro PD
models, displaying TUDCA’s antioxidant qualities in both by preventing ROS production and lipid peroxidation through increased nuclear factor erythroid 2 related factor 2 (Nrf2) expression. TUDCA’s neuroprotective potential was replicated in vivo with the MPTP-induced mouse model, reverting ROS
production caused by MPTP and increasing the expression of Nrf2 and Nrf2 downstream cytoprotective enzymes, glutathione peroxidase and heme oxygenase-1 [90]. Lastly, a rotenone-induced PD model using rats with daily intraperitoneal injections of UDCA resolved striatal dopamine content close to
the control group level and significantly downregulated nuclear factor-κB (NF-κB), BCL2 associated X apoptosis regulator (Bax) and caspase-9 mRNA levels. Striatal TNF-α and IL-1β levels that were significantly increased in the rotenone-treated group were attenuated in the UDCA administered group. Additionally, this UDCA treatment reduced rotenone-induced alterations of striatal neuron mitochondrial and increased striatal ATP to 2-fold above the control values [ 91 ]. PD research
implementing bile acid-mediated therapeutics has attenuated several harmful cellular mechanisms of this disease state."
