Table 1.
Model system and human data implicating bile acids in neurodegenerative disorders.
| Disease/Phenotype | Model | Bile acid | Mode of administration | Dose or concentration | Effects | References |
|---|---|---|---|---|---|---|
| Spinocerebellar ataxia type 1 (SCA1) | Transgenic mouse with human ATXN1 with 82 CAG trinucleotide repeats under control of a Purkinje-cell promoter | TUDCA | Subcutaneous injection | 500 mg/kg | TUDCA crossed the blood-brain barrier but had no effect on cell survival | Kaemmerer et al., 2001 |
| Huntington's disease (HD) | 3-nitropropionic acid-treated rat neuronal RN33B cells | TUDCA | Media | 100 μM | Decreased apoptosis by preventing mitochondrial depolarization and outer membrane disruption | Rodrigues et al., 2000 |
| GUDCA | 500 μM | |||||
| UDCA | 500 μM | |||||
| HD | 3-nitropropionic acid-treated rats | TUDCA | Intraperitoneal injection | 50 mg/kg | Decreased apoptosis | Keene et al., 2001 |
| Reduced lesion volume | ||||||
| Preserved sensorimotor and cognitive function | ||||||
| HD | R6/2 transgenic mouse with 150 CAG trinucleotide repeats in exon 1 of the huntingtin gene | TUDCA | Subcutaneous injection | 500 mg/kg | Reduced striatal cell apoptosis | Keene et al., 2002 |
| Decreased levels of intracellular inclusions | ||||||
| Improved locomotor and sensorimotor function | ||||||
| Parkinson's disease (PD) | Sodium nitroprusside-treated human dopaminergic SH-SY5Y cells | UDCA | Media | 50–200 μM | Dose dependent inhibition of apoptosis via the PI3K- | Chun and Low, 2012 |
| Akt/PKB pathways | ||||||
| Reduced ROS and reactive nitrogen species | ||||||
| Maintained intracellular GSH levels | ||||||
| PD | Skin fibroblasts from PD patients | UDCA | Media | 10–100 nM | Restored mitochondrial function dependent upon glucocorticoid receptor activation and Akt phosphorylation | Mortiboys et al., 2013 |
| PD | MPTP-induced mouse model | TUDCA | Intraperitoneal injection | 50 mg/kg | Reduction in loss of dopaminergic neurons by preserving levels of phosphorylated JNK, reducing ROS levels, and activating the Akt pathway | Castro-Caldas et al., 2012 |
| Alzheimer's disease (AD) | Aβ-treated primary rat cortical neurons | TUDCA | Media | 100 μM | Decreased nuclear fragmentation and cytochrome c release through the PI3K pathway | Solá et al., 2003 |
| AD | Aβ-treated mouse BV-2 microglial cells | UDCA | Media | 250 μM | Anti-inflammatory effect by inhibiting NF-κB activation | Joo et al., 2004 |
| AD | Aβ-treated primary rat cortical neurons | UDCA TUDCA | Media | 100 μM | Decreased apoptosis dependent on interaction with the mineralocorticoid receptor | Sola et al., 2006 |
| AD | Double transgenic APP/PS1 mice | TUDCA | Diet | 0.4% wt/wt | Reduced amyloid plaque number | Nunes et al., 2012; Ramalho et al., 2013 |
| Decreased injury to neurons | ||||||
| Improved memory retention | ||||||
| Decreased the loss of a postsynaptic marker in the hippocampus | ||||||
| Amyotrophic lateral sclerosis (ALS) | Mouse NSC-34 cells with the human SOD1G93A mutation | GUDCA | Media | 50 μM | Decreased cell death by blocking caspase-9 activation | Vaz et al., 2015 |
| ALS | Primary mouse ventral midbrain cultures | CA | Media | 10 μM | Increased neuronal survival and promoted neurogenesis via LXR | Theofilopoulos et al., 2013 |
| ALS | Clinical trial with ALS patients | UDCA | Oral | Up to 50 mg/kg | UDCA is well tolerated and well absorbed by oral administration | Parry et al., 2010 |
| UDCA crosses the blood-brain barrier in a dose-dependent manner | ||||||
| ALS | Clinical trial with ALS patients | UDCA | Oral | 3.5 g/140 mL/day | Slight decrease in progression of ALS but results were inconclusive | Min et al., 2012 |
| ALS | Clinical trial with ALS patients | TUDCA | Oral | 1 g, twice daily | TUDCA is well tolerated | Elia et al., 2016 |
| Treatment resulted in improved function and slowed disease progression | ||||||
| Prion disease | Prion infected male mice | UDCA | Diet | 0.01% wt/wt | Reduced astrogliosis | Cortez et al., 2015 |
| Prolonged survival | ||||||
| Cerebrotendinous xanthomatosis (CTX) | Human patients | CDCA | Oral | 15 mg/kg/day | Amelioration of neurological symptoms | Bjorkhem, 2013 |
| Improved prognosis | ||||||
| Retinitis pigmentosa (RP) | Homozygous P23H rhodopsin transgenic rats | TUDCA | Intraperitoneal injection | 500 mg/kg | Reduced photoreceptor loss | Fernandez-Sanchez et al., 2011 |
| Preserved structure, function, and synaptic contacts of rods and cones | ||||||
| RP | Transgenic rd10 mouse model | TUDCA | Subcutaneous injection | 500 mg/kg | Higher cone cell density from decreased apoptosis Preserved structure and function of photoreceptor cells | Boatright et al., 2006; Phillips et al., 2008; Oveson et al., 2011 |
| Light-induced retinal degeneration | Light-induced retinal damage (LIRD) mouse model | TUDCA | Subcutaneous injection | 500 mg/kg | Higher cone cell density from decreased apoptosis Preserved structure and function of photoreceptor cells | Boatright et al., 2006; Phillips et al., 2008; Oveson et al., 2011 |
| Leber congenital amaurosis | Homozygous LRAT knockout mice | TUDCA | Subcutaneous injection | 500 mg/kg | Slowed cone degeneration in the ventral and central retina by preventing apoptosis and increasing ER-associated protein degradation | Zhang et al., 2012; Fu and Zhang, 2014 |
| In vitro retinal degeneration | Whole mount cat retinas | TUDCA | Media | 0.5 μM | Greater receptive field size | Xia et al., 2015 |
| Decreased irradiance threshold | ||||||
| Maintenance of the contrast threshold | ||||||
| Retinal dystrophy | Primary human retinal epithelium cells | TUDCA | Media | 100 μM | Protective against H2O2-induced impairment of phagocytosis | Murase et al., 2015 |
| Retinal detachment | Subretinal injection of hyaluronic acid in rats | TUDCA | Intraperitoneal injection | 500 mg/kg | Reduced apoptosis in the outer nuclear layer of the retina | Mantopoulos et al., 2011 |
| Decreased caspase activation and protein carbonyl production | ||||||
| Diabetic retinopathy | Primary rat retinal neuron cells exposed to elevated glucose | TUDCA | Media | 100 μM | Decreased apoptosis | Gaspar et al., 2013 |
| Decreased mito-nuclear translocation of apoptosis-inducing factor (AIF) | ||||||
| Decreased ROS and protein carbonyl production | ||||||
| Retinal ganglion cell degeneration | Intravitreal injection of NMDA in rats | TUDCA | Intraperitoneal injection | 500 mg/kg | Increased survival of retinal ganglion cells | Gomez-Vicente et al., 2015 |
| Ischemic stroke | Middle cerebral artery occlusion in rats | TUDCA | Intravenous injection | 400 mg/kg | Reduction in infarct size | Rodrigues et al., 2002 |
| Reduced apoptosis | ||||||
| Preserved mitochondrial integrity | ||||||
| Hemorrhagic stroke | Collagenase | TUDCA | Intra-arterial injection | 200 mg/kg | Decreased lesion volumes, peri-hematoma apoptosis, caspase activity, NF-κB activiation; increased AKT activation, neurobehavioral improvement | Rodrigues et al., 2003 |
| Acute neuroinflammation | Intracerebro-ventricular injection with LPS in mice | TUDCA | Intraperitoneal injection | 500 mg/kg | Reduced glial cell activation | Yanguas-Casás et al., 2014 |
| Acute neuroinflammation | Primary cultures of microglial cells and astrocytes from rats treated with LPS and/or IFN-γ | TUDCA | Media | 200 μM | Reduced microglial chemotaxis and expression of MCP-1 and VCAM-1 | Yanguas-Casás et al., 2014 |
| Sleep-wake pattern | Wild type and histamine deficient mice | UDCA | Diet | 32 mg/kg | Promotes wakefulness through disinhibition of the histaminergic system via GABAA receptors | Yanovsky et al., 2012 |
| Hypothalamic network activity | Primary cultures of mouse posterior hypothalamus | CA | Media | Up to 8 mM | Reduced firing, synchronized network activity, and blocked GABAA and NMDA receptor activity | Schubring et al., 2012 |
| GCA | ||||||
| TCA | ||||||
| DCA | ||||||
| TDCA | ||||||
| CDCA | ||||||
| GCDCA | ||||||
| TCDCA | ||||||
| DHCA | ||||||
| Neurotransmitter release | Sympathetic ganglion neurons isolated from of adult bull frogs | CA | Media | 1 μM | Inhibits N-type calcium channel currents | Lee et al., 2012 |
| Hyperbilirubinemia | Unconjugated bilirubin-treated organotypic-cultured hippocampal slices from rats | GUDCA | Media | 50 mM | Decreased cell death, NOS, glutamate release | Silva et al., 2012 |
| Glutamate-induced neurotoxicity | Glutamate-treated primary rat cortical neurons | TUDCA | Media | 100 μM | Decreased apoptosis by activating a PI3K-dependent Bad signaling pathway | Castro et al., 2004 |