An Update on Role of Bile Acids in Neurological Functions and Neurodegenerative Diseases: A Narrative Review

Kulvinder Kochar Kaur^1*, Gautam Nand Allahbadia², Mandeep Singh^3
1Scientific Director, Dr Kulvinder Kaur Centre for Human Reproduction, Jalandhar, Punjab, India.
²Scientific Director, Ex-Rotunda-A Centre for Human Reproduction, Bandra, Mumbai, India.
³Consultant Neurologist, Swami Satyanand Hospital, Jalandhar, Punjab, India.

Correspondence to: Kulvinder Kochar Kaur, Scientific Director, Dr Kulvinder Kaur Centre for Human Reproduction, Jalandhar, Punjab, India.
Received date: August 30, 2023; Accepted date: September 20, 2023; Published date: September 27, 2023
Citation: Kaur KK, Allahbadia GN, Singh M. An Update on Role of Bile Acids in Neurological Functions and Neurodegenerative Diseases: A Narrative Review. J Clin Biomed Invest. 2023;3(2): 22-39. doi: 10.52916/jcbi234026
Copyright: ©2023 Kaur KK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Abstract

Having previously reviewed the role of Bile Acids (BAs) in obesity, NAFLD/NASH/HCC and crosstalk of Gut Microbiome in numerousbody disorders here we further attempted to assess part of BAs in normal brain physiology and in different Neurodegenerative Diseases (NDD). BAs constitute significant physiological molecules which apart from modulating nutrient absorption as well as metabolism in peripheral tissues influence neuromodulatory actions in the Central Nervous System (CNS). The formation of bile acids takes place basically from cholesterol in the liver by the canonical as well as alternate pathwaysor in the brain started by the neuron particular sterol Cholesterol-24 hydroxylase (CYP46A1) modulated pathway. Circulating BAs possess the capacity of crossing the Blood Brain Barrier (BBB) and thus gaining entry into the CNS via passive diffusion orthrough BAs transporters. Brain BAs act in the CNS via activationof membrane or nuclear receptors or influence the working of the neurotransmitter receptors. Indirect signal might be further given to the CNS through the Farsenoid X Receptor (FXR) based Fibroblast growth factor 15/19 (FGF15/19) pathway or the takeda G Protein Coupled (GPC) bile acid receptor 5 (TGR5) based Glucagon Like Peptide 1(GLP) pathway. In case of pathological situations, changes in BAs have been observed to probably aid in the pathogenesis of different neurological diseases. Of greater significance is the supplementationof hydrophilic amidated Ursodeoxycholic Acid (UDCA) or Tauroursodeoxycholic Acid (TUDCA) have been corroborated to illustrate therapeutic advantagesby hampering the neuroinflammatory reactions, apoptosis, Oxidative Stress (OS), Endoplasmic Reticulum (ER) stress, mitochondrial protection or work in the form of probable chaperone for correction of misfolding of proteins in the treatment of different neurological diseases.This yields opportunity of utilization of UDCA along with TUDCA in the treatment of different neurodegenerative diseases inclusive of Alzheimer’sdisease; Parkinson’s disease, Huntingtons disease, Amyotrophic Lateral sclerosis,and prion disease.

Keywords

Bile Acids (BAs), Cholesterol metabolism, Neurodegenerative diseases, Ursodeoxycholic Acid (UDCA), Tauroursodeoxycholic Acid (TUDCA)

References

1. Chiang JYL, Ferrell JM. Bile Acids as metabolic regulators and nutrient sensors. Annu Rev Nutr. 2019;39(4):175-200.
2. Ciaula AD, Garruti G, Baccetto RL, et al. Bile Acid physiology. Ann Hepatol. 2017;16(Suppl.1:s3-105.):s4-s14.
3. Kaur KK, Allahbadia GN, Singh M. MUtilization of Clostridium Species as Probiotics as an Alternative to the Conventional Probiotics like Lactobacillus rhamnosus/Bifidobacterium-How Far is it Feasible-A Systematic Review. J Endocrinol. 2021;5(1):1-12.
4. Kaur KK. Delivered a talk on 30th September on ’Advantages and Limitations of utilizing Clostridium species as Probiotics-ASytematic Review’’ in a webinar held by Gastroenterology conference on 30th September 2021.
5. Kaur KK, Allahbadia GN, Singh M. Mode of Actions of Bile Acids in Avoidance of Colorectal Cancer Development and Therapeutic Applications in Treatment of Cancers-A Narrative Review. J Pharm Nutr Sci. 2022;12:1-19.
6. Kaur KK, Allahbadia GN, Singh M. An update on the Association of Gut-Liver Axis with Gut Microbiome Dysbiosis Correlated NAFLD along with NAFLD- HCC with Potential Therapeutic Approaches:a systematic review. J Hepatol Gastroint Dis. 2022;8(6):1-9.
7. Xing C, Huang X, Wang D, et al. Role of Bile Acids signaling in neuromodulation under physiological and pathological conditions. Cell Biosci. 2023;13(1):125.
8. Russell DW. The enzymes, regulation, and genetics of bile acids synthesis. Annu Rev Biochem. 2003;72(7):137-174.
9. Takahashi S, Fatumi T, Masuo Y, et al. Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J Lipids Res. 2016;57(12):2130-2137.
10. Hoffmann AF, Hagey LR. Bile Acids chemistry, patho chemistry, biology, pathobiology and therapeutics. Cell Mol Life Sci. 2008;65(16):2461-2483.
11. Eggert T, Bakonyl D, Hummel W. Enzymatic routes for the synthesis of ursodeoxycholic acid. J Biotechnol. 2014;191(12):11-21.
12. Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipids Res. 2015;56(6):1085-1099.
13. Dawson PA. Hummert M, Haywood J, et al. The heteromeric organic solute transporter alpha beta, Ost alpha Ostbeta is an ileal basolateral bile acid transporter. J Biol Chem. 2015;280(8):6960-6968.
14. Shwarz M, Russell DW, Dietschy JM, et al. Marked reduction in bile acids synthesisin cholesterol -7 α hydroxylase- deficient mice does not lead to diminished tissue cholesterol turnover or hypercholesterolemia. J Lipids Res. 1998;39(9):1833-1843.
15. Rizzolo D, Buckley K, Kong B, et al. Bile Acid homeostasis in a cholesterol -7 α hydroxylase and sterol 27α hydroxylase double knockout mouse model. Hepatology. 2019;70(1):389-402.
16. Rizzolo D, Kong B,Taylor RE, et al. Bile Acid homeostasis in mice deficient in Cyp 7a1 and Cyp 27a1. Acta Pharm Sin B. 2021;11(12):3847-3856.
17. Bjorkhem I, Meaney S. Brain cholesterol:long secret life behind a barrier. Arterioscler Thromb Vasc Biol. 2004;24(5):806-815.
18. Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell. 2015;6(4):254-264.
19. Lund EG, Gulleyard JM, Russell DW. cDNA cloning of Cholesterol -24hydroxylase,a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci USA. 1999; 96(3):7238-7243.
20. Bjorkhem I, Andersson U, Ellis E, et al. From brain to bile: evidence that conjugation and omega hydroxylation are important for elimination of 24 Shydroxy cholesterol (cerebrosterol) in humans. J Biol Chem. 2001;276(40):37004-37010.
21. Lund EG, Xie C, KottiT, et al. Knockout of Cholesterol -24hydroxylase gene in mice reveals a brain specific mechanismof cholesterol turnover. J Biol Chem. 2003;278(25):22980-22988.
22. Bloussicault L, Alves S, Lamaziere A, et al. CYP46A1, the rate limiting enzymefor cholesterol degradation ,is neuroprotective in Huntingtons disease. Brain. 2016;139(Pt3):953-970.
23. Ali Z, Heverin M, Olin M, et al. On the regulatory role of side chain hydroxylated oxysterols in the brain:lessons from CYP7A1transgenic and Cyp 27a1(-/-)mice. J Lipids Res. 2013;54(4):1033-1043.
24. Meaney S, Heverin M, Panzenboeck U, et al.Novel route for elimination of brain oxysterols across the blood brain barrier : conversion into 7--α- hydroxy-cholesten-3-oxo-4 cholestenoic acid. J Lipids Res. 2007;48(4):944-951.
25. Bavner A,Shafaati M, Hansson M, et al. On the mechanism of accumulation of cholestanol in the brain of mice with disruption of sterol 27α hydroxylase. J Lipids Res. 2010;51(9):2722-2730.
26. Wu Z, Martin KO, Javitt NB, et al. Structure and function of human oxysterol 7α-hydroxylase cDNAs and gene CYP7B1. J Lipids Res. 1999;40(12):2195-2203.
27. Ridlon JM, KangDJ, Hylemon PB. Bile salts biotransformations byhuman intestinal bacteria. J Lipids Res. 2006;47(2):241-259.
28. Ridlon JM, KangDJ, Hylemon PB.Consequence of bile salts biotransformations by intestinal bacteria. Gut Microbes. 2016;7(1):22-39.
29. Molinero N, Ruiz L, Sanchez B, et al. Intestinal bacteriainterplay with bile acid and cholesterol metabolism: implications on host physiology. Front Physiol. 2019;10(3):185.
30. Saylin SI, Wahlstorm A, Felin J, et al. Gut microbiotaregulates bile acid by reducing the levels of tauroβmuricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17(2):225-235.
31. Park J, Kim CH. Regulation of commonneurological disorders by gut microbial metabolites. Exp Mol Med. 2021;53(12):1821-1833.
32. Mano N, Goto T, Uchida M, et al. presence of protein unconjugated bile acids in the cytoplasmic fractionof rat brain. J Lipids Res. 2004;45(2):295-300.
33. Baloni P, Funk CC,Yan J, et al. Metabolic network analysis reveals altered bile acids synthesis and metabolism in Alzheimer’sdisease. Cell Rep Med. 2020;1(8):100138
34. Zheng SX, Chen T, Zhao A, et al. The brain metabolome of male rats across the lifespan. Sci Rep. 2016;6(4):24125.
35. Pan X, Elliot CT, McGuinness B, et al. Metabolomic profiling of bile acids in Clinical and experimental samples of Alzheimer’sdisease. Metabolites. 2017;7(2):28.
36. Kitazawa T, Terasaki T, SuzukiH, et al. Efflux of taurocholic acid across the blood brain barrier:interactions with cyclic peptides. J Pharmacol Exp Ther. 2018;367:373-388.
37. Palmela I, Correia L, Silva RF, et al. Hydrophilic bile acidsprotect human blood brain barrier endothelial cells from disruption by unconjugated bilirubin:an in vitro study. Front Neurosci. 2015;9:80.
38. Higashi T, Watanabe S, Tomaru K, et al. Unconjugated bile acids in rat brain: analyticalmethod based on LC/ESI -MS/MS with chemical derivatization andestimation of their origin by comparison to serum levels. Steroids. 2017;125:107-113.
39. Choudhari S, Cherrington NJ, Li N, et al. Constitutive expression of xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab Disp. 2003;31(11):1337-1345.
40. OseA, Kusuhara H, Endo C, et al. Functional characterization of organic anion transporting polypeptide 1a4 in the uptake and efflux of drugs across blood brain barrier. Drug Metab Disp. 2010;38(1):168-176.
41. Nizamudiditnov D, De Morrow S, McMillin M, et al. Hepatic alterations are accompanied by changes to the bile acids expressing neurons in the hypothalamus after traumatic brain injury. Sci Rep. 2017;4(1):40112.
42. Perino A, Velasquez-Villegas LA, Bresconi N, et al. Central anorexogenic actions of bile acids are mediated by TGR5. Nat Med. 2021:3(5):595-603.
43. Greenwood J, Adu J, Davey AJ, et al. The effectsof bile salts on the permeability and ultrastructure of the perfused energy depleted rat blood brain barrier. J Cereb Blood Flow Metab. 1991;11(4):644-655.
44. Quinn M , McMillin M, Galindo C, et al. Bile acid signaling is permeabilize the blood brain barrier after bile duct ligation in rat via Rac1 dependent mechanisms. Dig Liver Dis. 2014;46(6):527-534.
45. Grant SM, DeMellowS. Bile acids signaling in Neurodegeneratiive and neurological disorders. Int J Mol Sci. 2020;21(17):5982.
46. Schaap FG, Trauner M, Janett PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11(1):55-67.
47. Huang F, WangT, HuW, et al. Identification of Farsenoid X receptors in brain neurons. FEBS Lett. 2016; 590(18):2233-2243.
48. McMillin M, Frampton G, Quinn M, et al. Bile acids signaling is involved in the neurological decline in a murine model of acute liver injury. Am J Pathol. 2016;186(2):312-323.
49. Huang F, Wang T, Lan Y, et al. Deletion of mouse FXR gene disrupts multiple neurotransmitter systems and altersneurobehaviour. Front Behav Neurosci. 2015;9(3):70.
50. de Oca Balderas PM. Flux-independent NMDAR signaling , molecular mediators, cellular functions and complexities. J Mol Sci. 2018;19(12):3800.
51. Cicek S. Structure dependent activity of natural GABA A receptor modulator. Molecules. 2018;23(7):1516.
52. Liao WL, Heo GY, Dodder NG, et al. Quantification of cholesterol metabolizingP450s CYP27A1 and CYP46A1 in neural tissues reveals a lack of enzyme product correlations in human retina but not in human brain. J Proteome Res. 2011;10(1):241-248.
53. Schubring SR, Fleischer W, Lin JS, et al. The bile chenodeoxycholate is a steroid potent antagonist at NMDA and GABA (A) receptors. Neurosci Lett. 2012;506(2):322-326.
54. Xie JF, Fan K, Wang C, et al. Inactivation of tuberomammilary nucleus by GABA (A) receptors agonist promote slow wave sleepin freely moving rats and histamine treated rats. Neurochem Res. 2017;42(8):2314-2325.
55. YanovskyY, Schubring SR, YaoQ, et al. Waking actions of Ursodeoxycholic Acid (UDCA) involves histamine and GABA A receptor block. PLOS ONE. 2012;7(8):e42512.
56. Xavier JM, Morgado AL, Rodriques CM, et al. Tauroursodeoxycholic acid increases neural stem cell pool and neuronal conversation by regulating mitochondrial cell cycle reterograde signaling. Cell Cycle. 2014;13(22):3576-3580.
57. Soares R, Ribeiro FF, Xapelli S, et al. Tauroursodeoxycholic acid enhances mitochondrial biogenesis, neural stem cell pool and early neurogenesis in adult rats. Mol Neurobiol. 2018;55(5):3725-3738.
58. Mertens KL, Kalsbeek A, Soeters MR, et al. Bile acids signaling pathways from the enterohepatic circulation to the central nervous system. Front Neurosci. 2017;11(11):617.
59. Kliewer SA, Mangelsdorf DJ. Bile acids as hormones: the FXR- FGF 15/19 pathway. Dig Dis. 2018;33(3):327-331.
60. Gadaleta RM, MoschettaA. Metabolic messengers: Fibroblast growth factor 15/ 19. Nat Metab. 2019;1(6):588-594.
61. Hschou H, Pan W, Kastin AJ. Fibroblast growth factor 19 entry into brain. Fluid Barriers CNS. 2013;10(1):32.
62. Ryan KK, Kohli R, Gutteirez-Aquilar R, et al. Fibroblast growth factor-19 actions in the brain reduces food intake and body weight and improves glucose tolerance in malerats. Endocrinology. 2013;154(1):9-15.
63. Marcelin G, Jo YH, LiX, et al. Central actions of FGF19 reduces hypothalamic AgRP/ NPY neurons activity and improves glucose metabolism. Mol Metab. 2014;3(1):19-28.
64. Liu S, Marcelin G, Blouet C, et al. A gut- brain axis regulating glucose metabolism mediated by bile acids and competitive Fibroblast growth factor actions in the hypothalamus. Mol Metab. 2018;8:37-50.
65. Brighton CA,Rievaz J,Kuhre RE,Glass LL,S K,Holst JJ,etal. Bile Acids trigger GLP-1 release predominantly by accessing basolaterally located G protein coupled bile acid receptor 5. Endocrinology. 2015;156(11):3961-3970.
66. Ruttiman EB, Arnold H, Hillebrand JJ, et al. Intrameal hepatic portal and intraperitoneal infusions of glucagon like peptide 1 reduce spontaneous meal size in the rat by different mechanisms. Endocrinology. 2009;150(3):1174-1181.
67. Cork SC, Richards JE, Holt MK, et al. Distribution and characterization of glucagon like peptide 1 receptor expressing cells in the mouse brain. Mol Metab. 2015;4(10);718-731.
68. Kastin A, AkerstromV, PanW. Interactions of glucagon like peptide 1(GLP-1) with the blood brain barrier. J Mol Neurosci. 2002;18(1-2):7-14.
69. Borgmann D, Cigliieri E, Biglari N, et al. Gut- brain communication by distinct sensory neurons differently controls feeding and glucose metabolism. Cell Metab. 2021;33(7):1466-1482.
70. Punjabi M, Arnold H, Ruttiman EB, et al. Circulating glucagon like peptide 1(GLP) inhibit eating in malerats by acting in the hind brain without avoidance. Endocrinology. 2014;155(5):1690-1699.
71. Holst JJ. The physiology of glucagon like peptide 1. Physiol Rev. 2007;87(4):1409-1439.
72. Perez MJ, Briz O. Bile acid induced cell injury. World J Gastroenterol. 2009; 15(14):1677-1689.
73. Rose CF, Amodio P, Bajaj JS, et al. Hepatic encephalopathy:novel insights into classification, pathophysiology and therapy. J Hepatol. 2020; 73(6):1526-1547.
74. Xie G, Wang X, Jiang R, et al. Dysregulated bile acid signaling contributes to the neurological impairment in murine models of acute and chronic liver failure. E Bio Medicine. 2018;37(11):294-306.
75. Wiess N, Hilaire PBS, Colsch B, et al. Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy. J Hepatol. 2016;65(6):1120-1130.
76. Tripodi V, Contin M, Fernandez-MA, et al. Bile acid content inrat brain of common duct ligated rats. Ann Hepatol. 2012;11(6):930-934.
77. McMillin M, Frampton G, Grant S, et al. Bile acid mediated sphingosine-1- phosphate receptor-2- receptor signaling promotes neuroinflammation during hepatic encephalopathy in mice. Front Cell Neurosci. 2017;11:191.
78. Lane CA, Hardy J, Scott JM. Alzheimer’s disease. Eur J Neurol. 2018; 25(1):59-70.
79. Marksteiner J, Blasko I, Kemmler G, et al. Bile acid quantification of 20 plasma metabolites identifies lithocholic acid as a putative biomarker in Alzheimer’sdisease. Metabolomic. 2018;14(1):1.
80. Rose KA, Stapleton G, Dott K, et al.Cyp7b,a novel brain cytochrome P450catalyzes the synthesis of neurosteroid 7 α hydroxy Dehydroepiandrosterone and 7 α hydroxy pregnenolone. Proc NatlAcad Sci USA. 1997; 94(10):4925-4930.
81. Mahmoudian Dehkordi S, Arnold M, Nho K, et al. Altered bile acid profiles associates with cognitive impairment in Alzheimer’sdisease-an emerging role for Gut Microbiome. Alzheimer’s Dement. 2019;15(1):76-92.
82. Nho K, Kuider Paisley A, Mahmoudian Dehkordi S, et al. Altered bile acid profiles in mild cognitive impairment and Alzheimer’sdisease: relationship to Neuroimaging and CSF biomarkers. Alzheimer’s Dement. 2019;15(2):232-244.
83. Shao Y, Li T, Liu Z, et al. Comprehensive metabolic profiling of Parkinson’s disease by liquid chromatography-mass spectrometry. Mol Neurodegener. 2021;16(1):4.
84. Li P, Killinger BA, Ensink E, et al. Gut Microbiota dysbiosis is associated with elevated bile acids in Parkinson’s disease. Metabolites. 2021;11(1):29.
85. Yilmaz A, Ugur Z,Ustun I, et al. Metabolic profiling of CSF from people suffering from Sporadic andLRRK2 Parkinson’s disease:a pilot study. Cells. 2020;9(11):294.
86. Grahams SF, Rey NL, Ugur Z, et al. Metabolic profiling of bile acids in an experimental model of prodromal Parkinson’s disease. Metabolites. 2018;8(4):71.
87. McColgan P, Tabrizi S. Huntingtons disease: a clinical review. Eur J Neurol. 2018; 25(1):24-34.
88. Kacher R, Mounier C, Caboche J, et al. Altered cholesterol homeostasis in Huntingtons disease. Front Aging Neurosci. 2022;14:797220.
89. Leoni V, Long JD, Mills JA, et al. Group-P-Hs: plasma245- hydroxy cholesterol correlation with biomarkers of Huntingtons disease progression. Neurobiol Dis. 2013;55:37-43.
90. Verrips A, Van Englen BG, Wevers RA, et al. Presence of diarrhoea and absence of tendon xanthomas in patients with cerebrotendinous xanthomatosis. Arch Neurol. 2000;57(4):520-524.
91. Wong JC, Walsh K, Hayden D, et al. Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2018;41(4):647-656.
92. Nie S, Chen G, Cao X, et al. Cerebrotendinous xanthomatosis: a Comprehensive review of pathogenesis, Clinical manifestations, diagnosis and management. Orphanet J Rare Dis. 2014; 9:179.
93. Koyama S, Sekijima Y, Ogura M, et al. Cerebrotendinous xanthomatosis: molecular pathogenesis, Clinical spectrum, diagnosis and diseasemodifying rx. J Atheroscler Thromb. 2021; 28(9):905-925.
94. Stelten BML, Lycklama ANG, Hendricks E, et al. Long term MRI finding in patients with cerebrotendinous xanthomatosis treated with chenodeoxycholic acid. Neurol. 2022;99(13):559-566.
95. Khalaf K ,Tornese P, Cornese A, et al. Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases. Transl Neurodegener. 2022;11(1):33.
96. Matias I, Morgado J, Gomes FCA. Astrocytesheterogeneity: impactto brain aging and disease. Front Aging Neurosci. 2019;11:59.
97. Stephenson J, Nutrina E, van der Walk, et al. Inflammation in CNS neurodegenerative diseases. Immunology. 2018;154(2):204-9.
98. Joo SS, Kang HC, Won TJ, et al. Ursodeoxycholic acid inhibits proinflammatory repertoire, IL-1β and nitric oxide in rats microglia. Arch Pharmacol Res. 2003;26(12):1067-1073.
99. Joo SS, Won TJ, Lee DL. potential role of suppression of nuclear factor κappa B in microglial cell line(BV-2). Arch Pharmacol Res. 2004;27(9):954-960.
100. Jiang C, Shen T, Li K, et al. Protective effects of ursodeoxycholic acid against Oxidative stress and neuroinflammation through Mitogen Activated Protein Kinase (MAPK) in MPTP induced Parkinson’s disease. Clin Neuropharmacol. 2022;45(6):168-174.
101. Yanguas Cansas N, Barreda Manso N, et al. Tauroursodeoxycholic acid reduces glial activation in an animal model of acute neuroinflammation. J Neuroinflammat. 2014;11:50.
102. Yanguas Cansas N, Barreda Manso N, Perez Rial S, et al. TGF- beta contributes to the TUDCA anti-inflammatory effects of Tauroursodeoxycholic acid in an animal model of acute neuroinflammation. Mol Neurobiol. 2017;54(9): 6737-6749.
103. Yanguas Cansas N, Barreda Manso N, et al. TUDCA,anagonist of bile acid receptors GPBAR/TGR-5 with anti-inflammatory effects in microglial cells. J Cell Physiol. 2017;232(8):2231-2245.
104. Wu X, Liu C, Chen L, et al. Protective effects of tauroursodeoxycholic acid on lipopolysaccharide induced conitive impairment and neurotoxicity in mice. Int Immunopharmacol. 2019;72:166-175.
105. Sweis R, Biller J. Systemic complications of spinal cord Injury. Curr Neurol Neurosci Rep. 2017;17(2):8.
106. Kim SJ, Ko WK, Jo MJ, et al. Anti-inflammatory effects of tauroursodeoxycholic acid in RAW264.7 macrophages, Bone marrow-derived macrophages, BV-2 microglial cells and spinal cord Injury. Sci Rep. 2018;8(1):3176.
107. Romero Ramirez L, Garcia-Rama C, Wu S, et al. Bile Acids attenuate PKM2 pathway microglial activation in proinflammatory microglia. Sci Reports. 2022;12(1):1459.
108. Han GH, Kim SJ, Ko WK, et al. Injectable hydrogel containing tauroursodeoxycholic acid for anti - neuroinflammatory therapy after spinal cord Injury in rats. Mol Neurobiol. 2022;57(10):4007-4017.
109. Han GH, Kim SJ, Ko WK, et al. Transplantation of tauroursodeoxycholic acid transplantation of inducing M2 phenotype macrophages promote an anti-neuroinflammatory effect and functional recovery after spinal cord Injury in rats. Cell Prolif. 2021:54(6):e13050.
110. Wu S, Garcia-Rama C, Romero Ramirez L, et al. Tauroursodeoxycholic acid reduces neuroinflammation but does not support long term functional recovery of rats with spinal cord Injury. Biomed. 2022;10(7):1501.
111. Nunes AF, Amaral JD, Lo AC, et al. TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid beta deposition in APP/PSI mice. Mol Neurobiol. 2012;45(3):440-454.
112. Dionisio PA, Ribeiro MF, Lo AC, et al. Amyloid beta pathology is attenuated by tauroursodeoxycholic acid treatment in in APP/PSI mice after disease onset. Neurobiol Aging. 2015;36(1):228-240.
113. Cuevas E, Burks R, Raymick J, et al. Tauroursodeoxycholic Acid (TUDCA) is neuroprotective in a chronic mouse model of Parkinson’s disease. Nutr Neurosci. 2022;25(7):1374-1391.
114. Mendes MI, Rosa AI, Carvalho AN, et al. Neurotoxic effects of MPTP on mouse cerebral cortex : modulation of neuroinflammation as aneuroprotectivestrategy. Mol Cell Neurosci. 2019;96: 1-9.
115. Bhargava P,Smith MD, Mische L, et al. Bile Acids metabolism is altered in Multiple Sclerosis and supplementation ameliorates neuroinflammation. J Clin Investig. 2020;130(7):3467-3480.
116. Noailles A, Fernandez-Sanchez L, Lax P, et al. Microglial activation in a model of retinal degeneration and TUDCA neuroprotective effects. J Neuroinflammat. 2014;11:186.
117. Murase H, Tsuruma K, Shimazawa M, et al. TUDCA promotes phagocytosis by retinal pigment epithelium via MerTK activation. Invest Ophthalmol Vis Sci. 2015;56(4):2511-2518.
118. Radi E, Formichi P, Battisti C, et al. Apoptosis and Oxidative stressin neurodegenerative diseases. J Alzheimer’ Dis. 2014;42(Suppl3):125-152.
119. Viana RJ, Ramalho RM, Nunes AF, et al. Modulation of amyloid beta peptide induced toxicity through inhibition of JNK nuclear localization and caspase-2 activation. J Alzheimer’ Dis. 2010; 22 (2):557-568.
120. Ramalho RM, Boralho PM, Castro RE, et al. Tauroursodeoxycholic acid modulates p-53 mediated apoptosisin Alzheimer’s disease mutant neuroblastoma cells. J Neurochem. 2006;98(5):1610-1618.
121. Rodriques CM, Sola S, Brito MA, et al. Amyloid beta peptide disrupts mitochondrial membranelipid and protein structure: protective role of tauroursodeoxycholic acid. Biochim Biophys Res Commun. 2001;281(2):468-474.
122. Sola S, Castro RE, Laires PA, et al. Tauroursodeoxycholic acid prevents amyloid beta peptide induced neuronal death via a phosphatidyl inositol 3-kinase dependent signaling pathway. Mol Med. 2003;3(9-12):226-234.
123. Sola S, Amaral JD, Boralho PM, et al. Functional modulation of nuclear steroid receptors by tauroursodeoxycholic acid reduces amyloid beta peptide induced apoptosis. Mol Endocrinol. 2006;20(10):2292-2303.
124. Ramalho RM, Viana RJ, Low WC, et al. Bile Acids and apoptosis modulation: an emerging role in experimental Alzheimer’sdisease. Trends Mol Med. 2008;14(2):54-62.
125. Lo AC, Callaerts-Vegh Z, Nunes AF, et al. Tauroursodeoxycholic Acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PSI mice. Neurobiol Dis. 2013;50:21-29.
126. DuanWM, Rodriques CM, Zhao LR, et al. Tauroursodeoxycholic acid improves the survival and function of nigral transplants in a rat model of Parkinson’s disease. Cell Transplant. 2002;11(3):195-205.
127. Keene CD, Rodriques CM,Eich T, et al. A bile acid protects against motor and cognitive deficits and reduces striatal degeneration in the 3-nitrolpropionic acid model of Huntingtons disease. Exp Neurol. 2001;171(2):351-360.
128. Keene CD, Rodriques CM, Eich T, et al. Tauroursodeoxycholic acid,a bile acid is neuroprotective in a transgenic model of Huntingtons disease. Proc Natl Acad Sci USA. 2002;99(16):10671-10676.
129. Dong Y, Miao L, Hei L, et al. Neuroprotective effects and impact on caspase-12 expression of tauroursodeoxycholic acid after spinal cord Injury in rats. Int J Exp Pathol. 2015;8(12):15871-15878.
130. Chang Y,Yang T, Ding H, et al. Tauroursodeoxycholic acid protects rats spinal cord neurons after mechanical injury through regulating neuronal autophagy. Neurosci Lett. 2022;776(2):136578.
131. Hulisz D. Amyotrophic Lateral sclerosis: disease state overview. Am J Manage Care. 2018;24(15Suppl):S320-S326.
132. Kaur KK,Allahbadia GN, Singh M. A Comprehensive Update on the Etiopathogenesis of Amyotrophic Lateral Sclerosis with Specific Emphasis on Gut Microbiota (GM), Enteric Nervous System (ENS) and Associated Crosstalk of Astrocytes, GM, Muscle with Mitochondrial Melatonergic Pathway-A Narrative Review. Int J Neurobiol. 2023;5(2):158.
133. Min JH, Hong YH, Song JJ, et al. Oral solubilized ursodeoxycholic acid therapy in Amyotrophic Lateral sclerosis:a randomizedcrossover trial. J Korean Med Sci. 2012;27(2):200-206.
134. Thams S, Lowry ER, Larraufi MH, et al. A stemcells screening platform identifies compounds that desensitizes motor neurons to Endoplasmic Reticulum (ER) stress. Mol Ther. 2019;27(1):87-101.
135. Vaz AR, Cunha C, Gomes C, et al. Glyco Ursodeoxycholic Cholic Acid(GCDCA) reduces Matrix Metalloproteinase-9 and caspase-9 in a cellular model of superoxide dismutase-1 neurodegeneration. Mol Neurobiol. 2015;51(3):864-877.
136. Rosa AI, Duarte Silva S, Silva-Fernandez A, et al. Tauroursodeoxycholic acid improves motor in a mouse model of Parkinson’s diseas. Mol Neurobiol. 2018;55(12):9139-9155.
137. Rosa AI, FonsecaI, Nunes MJ, et al. Novel insight into the antioxidant role of tauroursodeoxycholic acid in experimental models of Parkinson’s disease. Biochem J Biochim Biophys Acta Mol Basis Dis. 2017;1863(9):2171-2181.
138. Moreira S, FonsecaI, Nunes MJ, et al. Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson’s disease. Exp Neurol. 2017;295:77-87.
139. Castro-Caldas M, Carvalho AN, Rodriquez E, et al. Tauroursodeoxycholic acid prevents MPTP induced dopaminergiccell death in a mouse model of Parkinson’s disease. Mol Neurobiol. 2012;46(2):475-486.
140. Kasaczuk M. Tauroursodeoxycholic acid: Bile acid with chaperoning activity: molecular and cellular effects and therapeutic perspectives. Cells. 2019;8(12):1471.
141. Van der Harg JM, Nolle A, Zwart R, et al. The Unfolded proteins response mediates reversibletau phosphorylation induced by metabolic stress. Cell Death Dis. 2014;5(8):e1393.
142. Macedo B, Batista AR, Ferreira N, et al. Anti apoptotic treatment reduces transthyretin deposition in a transgenicmouse model transthyretin deposition of familial amyloidotic polyneuropathy. Biochim Biophys Acta. 2008;1782(9):517-522.
143. Zattoni M, Legname G. Tackling prion disease:a review of patent landscape. Exp Opin Ther Pat. 2021;31(12):1097-1115.
144. Cortez M, Campeau J, Norman G, et al. Bile acids reduce prion conversion, reduce neuronal loss andprolong male survival in models of prion disease. J Virol. 2015;89(15):7660-7672.
145. Norman G, Campeau J, Sim VL. High doses and delayed treatment with Bile acid is ineffective in RML prion infected mice. Antimicrob Agents Chemother. 2018;62(8):e00222-e00318.
146. KIiriyama Y, Nochi H. Bile Acid Role of Microbiota Bile Acids in the regulation of intracellular organelles and neurodegenerative diseases. Genes (Basel). 2023;14(4):825.
147. Rusch JA, Layden BT, Dugas LR. Signaling cognition: the GutMicrobiota and hypothalamo-pituitary-adrenal axis. Front Endocrinol (Lausanne). 2023;14:1130689.