taurochenodeoxycholic-acid and Nerve-Degeneration

Bile acids are produced in the liver and excreted into the intestine, where their main function is to participate in lipid digestion. Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have shown antiapoptotic, anti-inflammatory, and antioxidant effects in various models of neurodegenerative diseases. However, little is known about signaling pathways and molecular mechanisms through which these bile acids act as neuroprotectors, delaying translation to the clinical setting. We review evidence supporting a potentially therapeutic role for bile acids in retinal disorders, and the mechanisms and pathways involved in the cytoprotective effects of bile acids from the liver and the enterohepatic circulation to the central nervous system and the retina. As secondary bile acids are generated by the microbiota metabolism, bile acids might be a link between neurodegenerative retinal diseases and microbiota.

Topics: Animals; Cytoprotection; Humans; Nerve Degeneration; Neuroprotective Agents; Retinal Diseases; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid

Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid derivative, which has been demonstrated to have neuroprotective effects in different neurological disease models. However, the effect and underlying mechanism of TUDCA on spinal cord injury (SCI) have not been fully elucidated. This study aims to investigate the protective effects of TUDCA in the SCI mouse model and the related mechanism involved.. We found that TUDCA attenuated axon degeneration induced by H. TUDCA treatment can alleviate secondary injury and promote functional recovery by reducing oxidative stress, inflammatory response, and apoptosis induced by primary injury, and promote axon regeneration and remyelination, which could be used as a potential therapy for human SCI recovery.

Topics: Animals; Apoptosis; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Nerve Degeneration; Nerve Regeneration; Neuroprotective Agents; Oxidative Stress; Recovery of Function; Spinal Cord Injuries; Taurochenodeoxycholic Acid

Parkinson's disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Gait; Hindlimb; Homeostasis; Inflammation; Male; Mice; Mice, Inbred C57BL; Mitochondria; Motor Activity; Movement; Neostriatum; Nerve Degeneration; Neuroglia; Neuroprotective Agents; Parkinson Disease; Taurochenodeoxycholic Acid; Tremor

Mitochondrial dysfunction and oxidative stress are implicated in the neurodegenerative process in Parkinson's disease (PD). Moreover, c-Jun N-terminal kinase (JNK) plays an important role in dopaminergic neuronal death in substantia nigra pars compacta. Tauroursodeoxycholic acid (TUDCA) acts as a mitochondrial stabilizer and anti-apoptotic agent in several models of neurodegenerative diseases. Here, we investigated the role of TUDCA in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in a mouse model of PD. We evaluated whether TUDCA modulates MPTP-induced degeneration of dopaminergic neurons in the nigrostriatal axis, and if that can be explained by regulation of JNK phosphorylation, reactive oxygen species (ROS) production, glutathione S-transferase (GST) catalytic activation, and Akt signaling, using C57BL/6 glutathione S-transferase pi (GSTP) null mice. TUDCA efficiently protected against MPTP-induced dopaminergic degeneration. We have previously demonstrated that exacerbated JNK activation in GSTP null mice resulted in increased susceptibility to MPTP neurotoxicity. Interestingly, pre-treatment with TUDCA prevented MPTP-induced JNK phosphorylation in mouse midbrain and striatum. Moreover, the anti-oxidative role of TUDCA was demonstrated in vivo by impairment of ROS production in the presence of MPTP. Finally, results herein suggest that the survival pathway activated by TUDCA involves Akt signaling, including downstream Bad phosphorylation and NF-κB activation. We conclude that TUDCA is neuroprotective in an in vivo model of PD, acting mainly by modulation of JNK activity and cellular redox thresholds, together with activation of the Akt pro-survival pathway. These results open new perspectives for the pharmacological use of TUDCA, as a modulator of neurodegeneration in PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; bcl-Associated Death Protein; Cell Death; Disease Models, Animal; Dopaminergic Neurons; HSP27 Heat-Shock Proteins; I-kappa B Proteins; Intracellular Space; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Degeneration; Neuroprotective Agents; NF-kappa B; NF-KappaB Inhibitor alpha; Parkinson Disease; Phosphorylation; Reactive Oxygen Species; Taurochenodeoxycholic Acid

Huntington's disease (HD) is an untreatable neurological disorder caused by selective and progressive degeneration of the caudate nucleus and putamen of the basal ganglia. Although the etiology of HD pathology is not fully understood, the observed loss of neuronal cells is thought to occur primarily through apoptosis. Furthermore, there is evidence in HD that cell death is mediated through mitochondrial pathways, and mitochondrial deficits are commonly associated with HD. We have previously reported that treatment with tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, prevented neuropathology and associated behavioral deficits in the 3-nitropropionic acid rat model of HD. We therefore examined whether TUDCA would also be neuroprotective in a genetic mouse model of HD. Our results showed that systemically administered TUDCA led to a significant reduction in striatal neuropathology of the R6/2 transgenic HD mouse. Specifically, R6/2 mice began receiving TUDCA at 6 weeks of age and exhibited reduced striatal atrophy, decreased striatal apoptosis, as well as fewer and smaller size ubiquitinated neuronal intranuclear huntingtin inclusions. Moreover, locomotor and sensorimotor deficits were significantly improved in the TUDCA-treated mice. In conclusion, TUDCA is a nontoxic, endogenously produced hydrophilic bile acid that is neuroprotective in a transgenic mouse model of HD and, therefore, may provide a novel and effective treatment in patients with HD.

Topics: Animals; Apoptosis; Bile Acids and Salts; Cell Nucleus; Corpus Striatum; Disease Models, Animal; Huntington Disease; Male; Mice; Mice, Transgenic; Motor Activity; Nerve Degeneration; Neurons; Neuroprotective Agents; Taurochenodeoxycholic Acid

There is currently no effective treatment for Huntington's disease (HD), a progressive, fatal, neurodegenerative disorder characterized by motor and cognitive deterioration. It is well established that HD is associated with perturbation of mitochondrial energy metabolism. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, can stabilize the mitochondrial membrane, inhibit the mitochondrial permeability transition, decrease free radical formation, and derail apoptotic pathways. Here we report that TUDCA significantly reduced 3-nitropropionic acid (3-NP)-mediated striatal neuronal cell death in cell culture. In addition, rats treated with TUDCA exhibited an 80% reduction in apoptosis and in lesion volumes associated with 3-NP administration. Moreover, rats which received a combination of TUDCA + 3-NP exhibited sensorimotor and cognitive task performance that was indistinguishable from that of controls, and this effect persisted at least 6 months. Bile acids have traditionally been used as therapeutic agents for certain liver diseases. This is the first demonstration, however, that a bile acid can be delivered to the brain and function as a neuroprotectant and thus may offer potential therapeutic benefit in the treatment of certain neurodegenerative diseases.

Topics: Animals; Cell Death; Cells, Cultured; Cognition; Corpus Striatum; Disease Models, Animal; Female; Huntington Disease; Mitochondria; Motor Activity; Nerve Degeneration; Neurotoxins; Nitro Compounds; Propionates; Rats; Rats, Inbred F344; Taurochenodeoxycholic Acid