ursodoxicoltaurine and Spinal-Cord-Injuries

Bile acids, which are synthesized in liver and colon, facilitate the digestion of dietary lipids. In addition to this metabolic function, they also act as molecular signals with activities in the nervous system. These are mediated primarily by a G-protein-coupled bile acid receptor (known as TGR5). Preceded by a long tradition in Chinese medicine, bile acids are now being investigated as therapeutic options in several neuropathologies. Specifically, one bile acid, tauroursodeoxycholic acid (TUDCA), which passes the blood-brain barrier and shows anti-inflammatory and anti-apoptotic effects, has been tested in animal models of spinal cord injury (SCI). In this review, we discuss the evidence for a therapeutic benefit in these preclinical experiments. At the time of writing, 12 studies with TGR5 agonists have been published that report functional outcomes with rodent models of SCI. Most investigations found cytoprotective effects and benefits regarding the recovery of sensorimotor function in the subacute phase. When TUDCA was applied in a hydrogel into the lesion site, a significant improvement was obtained at 2 weeks after SCI. However, no lasting improvements with TUDCA treatment were found, when animals were assessed in later, chronic stages. A combination of TUDCA with stem cell injection failed to improve the effect of the cellular treatment. We conclude that the evidence does not support the use of TUDCA as a treatment of SCI. Nevertheless, cytoprotective effects suggest that different modes of application or combinatorial therapies might still be explored.

Topics: Animals; Models, Animal; Receptors, G-Protein-Coupled; Spinal Cord Injuries; Taurochenodeoxycholic Acid

To study the protective effect of tauroursodeoxycholic acid (TUDCA) on the spinal cord nerve cells (SCN) of SD rats and to explore the protective mechanism of TUDCA against mechanical injury of the SCN.. The SCN of SD rats were cultured in vitro, and a mechanical injury models of 1 mm, 3 mm, and 5 mm SCN were established. The cell survival rate was determined using the MTT assay to determine the optimal degree and time of injury. Different concentrations (0.5, to 20 mmol/L) of TUDCA were used to detect SCN cell survival rate after mechanical injury. MTT assay was used to determine the optimal TUDCA intervention dose. SCN autophagy in different experimental groups were observed by electron microscopy after the best degree of mechanical injury, time of injury, and TUDCA concentration. Beclin-1 and LC3 II/I expressions were detected by western blotting and immunohistochemistry.. Survival rate of SCN was close to 50% when the injury interval was 3 mm and the injury time was 24 h, significantly different from those of each group (P < 0.05). At 3 mm injury interval and 24 h injury time, SCN survival rate was approximately 80% when TUDCA concentration was 4 mmol/L, which was significantly different from those of each group (P < 0.05). Cell morphology of the normal control group was complete, with few autophagy lysosomes. Compared with the normal control group, the number of autophagic lysosomes in the mechanical injury group increased, and cell damage was more severe. Compared with the mechanical injury group, the number of autophagy lysosomes in the mechanical injury + TUDCA intervention group increased significantly, and cell damage was less severe. Further, compared with the normal control group, beclin-1 and lc3ii / I expressions in the mechanical injury group were significantly higher (P < 0.05); compared with the mechanical injury group, beclin-1 and lc3ii / I expressions in the mechanical injury + TUDCA intervention group were significantly higher (P < 0.05).. TUDCA can protect SCN from mechanical injury in vitro, which may be related to the enhancement of the expression of autophagy-related protein beclin-1 and LC3 II/I.

Topics: Animals; Autophagy; Neurons; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Taurochenodeoxycholic 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

In this study, we study the transplantation of tauroursodeoxycholic acid (TUDCA)-induced M2-phenotype (M2) macrophages and their ability to promote anti-neuroinflammatory effects and functional recovery in a spinal cord injury (SCI) model.. To this end, compared to the granulocyte-macrophage colony-stimulating factor (GM-CSF), we evaluated whether TUDCA effectively differentiates bone marrow-derived macrophages (BMDMs) into M2 macrophages.. The M2 expression markers in the TUDCA-treated BMDM group were increased more than those in the GM-CSF-treated BMDM group. After the SCI and transplantation steps, pro-inflammatory cytokine levels and the mitogen-activated protein kinase (MAPK) pathway were significantly decreased in the TUDCA-induced M2 group more than they were in the GM-CSF-induced M1 group and in the TUDCA group. Moreover, the TUDCA-induced M2 group showed significantly enhanced tissue volumes and improved motor functions compared to the GM-CSF-induced M1 group and the TUDCA group. In addition, biotinylated dextran amine (BDA)-labelled corticospinal tract (CST) axons and neuronal nuclei marker (NeuN) levels were increased in the TUDCA-induced M2 group more than those in the GM-CSF-induced M1 group and the TUDCA group.. This study demonstrates that the transplantation of TUDCA-induced M2 macrophages promotes an anti-neuroinflammatory effect and motor function recovery in SCI. Therefore, we suggest that the transplantation of TUDCA-induced M2 macrophages represents a possible alternative cell therapy for SCI.

Topics: Animals; Cells, Cultured; Female; Inflammation; Macrophages; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries; Taurochenodeoxycholic Acid

We investigate the anti-inflammatory effects of injectable hydrogel containing tauroursodeoxycholic acid (TUDCA) in a spinal cord injury (SCI) model. To this end, TUDCA-hydrogel (TC gel) is created by immersing the synthesized hydrogel in a TUDCA solution for 1 h. A mechanical SCI was imposed on rats, after which we injected the TC gel. After the SCI and injections, motor functions and lesions were significantly improved in the TC gel group compared with those in the saline group. The TC gel significantly decreased pro-inflammatory cytokine levels compared with the saline; TUDCA and glycol chitosan-oxidized hyaluronate were mixed at a ratio of 9:1 (CHA) gel independently. In addition, the TC gel significantly suppressed the phosphorylation of extracellular signal-regulated kinase (p-ERK) and c-Jun N-terminal kinase (p-JNK) in the mitogen-activated protein kinase (MAPK) pathway compared with the saline, TUDCA, and CHA gel independently. It also decreased tumor necrosis factor-α (TNF-α) and glial fibrillary acidic protein (GFAP), inflammatory marker, at the injured sites more than those in the saline, TUDCA, and CHA gel groups. In conclusion, the results of this study demonstrate the neuroinflammatory inhibition effects of TC gel in SCI and suggest that TC gel can be an alternative drug system for SCI cases.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Behavior, Animal; Chitosan; Cytokines; Glial Fibrillary Acidic Protein; Hyaluronic Acid; Hydrogels; Inflammation Mediators; Injections; MAP Kinase Signaling System; Motor Activity; Neuraminidase; Phosphorylation; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries; Taurochenodeoxycholic Acid; Tumor Necrosis Factor-alpha

Spinal cord injury (SCI) is generally divided into primary and secondary injuries, and apoptosis is an important event of the secondary injury. As an endogenous bile acid and recognized endoplasmic reticulum (ER) stress inhibitor, tauroursodeoxycholic acid (TUDCA) administration has been reported to have a potentially therapeutic effect on neurodegenerative diseases, but its real mechanism is still unclear. In this study, we evaluated whether TUDCA could alleviate traumatic damage of the spinal cord and improve locomotion function in a mouse model of SCI. Traumatic SCI mice were intraperitoneally injected with TUDCA, and the effects were evaluated based on motor function assessment, histopathology, apoptosis detection, qRT-PCR, and western blot at different time periods. TUDCA administration can improve motor function and reduce secondary injury and lesion area after SCI. Furthermore, the apoptotic ratios were significantly reduced; Grp78, Erdj4, and CHOP were attenuated by the treatment. Unexpectedly, the levels of CIBZ, a novel therapeutic target for SCI, were specifically up-regulated. Taken together, it is suggested that TUDCA effectively suppressed ER stress through targeted up-regulation of CIBZ. This study also provides a new strategy for relieving secondary damage by inhibiting apoptosis in the early treatment of spinal cord injury.

Topics: Animals; Apoptosis; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Male; Mice; Models, Biological; Motor Activity; Neurons; Recovery of Function; Repressor Proteins; Spinal Cord Injuries; Taurochenodeoxycholic Acid; Up-Regulation

This study aimed to investigate the anti-inflammatory effects of tauroursodeoxycholic acid (TUDCA) after spinal cord injury (SCI) in rats. We induced an inflammatory process in RAW 264.7 macrophages, BV2 microglial cells, and bone marrow-derived macrophages (BMM) using lipopolysaccharide (LPS). The anti-inflammatory effects of TUDCA on LPS-stimulated RAW 264.7 macrophages, BV2 microglial cells, and BMMs were analyzed using nitric oxide (NO) assays, quantitative real-time polymerase chain reactions (qRT-PCR), and enzyme-linked immunosorbent assays (ELISA). The pathological changes in lesions of the spinal cord tissue were evaluated by hematoxylin & eosin (H&E) staining, luxol fast blue/cresyl violet-staining and immunofluorescent staining. TUDCA decreased the LPS-stimulated inflammatory mediator, NO. It also suppressed pro-inflammatory cytokines of tumor necrosis factor-α (TNF-α), interleukin 1-β (IL-1β), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in both mRNA and protein levels. In addition, TUDCA decreased prostaglandin E

Topics: Animals; Anti-Inflammatory Agents; Bone Marrow Cells; Cytokines; Gene Expression Regulation; Macrophages; Mice; Microglia; Rats, Sprague-Dawley; RAW 264.7 Cells; RNA, Messenger; Spinal Cord Injuries; Taurochenodeoxycholic Acid

To investigate the impact and protective effect of tauroursodeoxycholic acid (TUDCA) on the autophagy of nerve cells in rats with acute spinal cord injury.. Seventy-two 6-8-week-old male Sprague-Dawley (SD) rats were selected and were randomly divided into a sham operation group, a saline control group and a TUDCA treatment group (high and low dose groups). The experimental animals were sacrificed at 24 hours, 5 days and 10 days after spinal cord injury. The Basso, Beattie, Bresnahan locomotor scale was used to assess the hind limb locomotor function after the rats were injured but before sudden death. Electron microscopy, hematoxylin and eosin (HE) staining, TUNEL assays and immunohistochemistry techniques were used to observe the autophagy of the cells. Western blotting was used to analyze the expression of the autophagy-related factor Beclin-1 and the apoptosis-related factor caspase-3, and reverse transcription polymerase chain reaction (RT-PCR) was used to analyze the mRNA expression levels of the above proteins.. The locomotor scores of the rats in the saline group were significantly reduced, their Beclin-1 expression levels in neurons were decreased, and caspase-3 expression was increased. The hind limb locomotor scores of rats in the TUDCA groups were decreased, with no difference between the high- and low-dose groups. Beclin-1 expression in their neurons was increased, and caspase-3 expression was decreased; there was a significant difference when compared with the control group, while there was no significant difference between the high- and low-dose groups.. TUDCA significantly activates the neuronal autophagic expression in rats with acute spinal cord injury to inhibit the apoptosis of nerve cells; therefore, it has a protective effect on neurons.

Topics: Animals; Apoptosis; Autophagy; Locomotion; Male; Neurons; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Taurochenodeoxycholic Acid

To observe the effects of tauroursodeoxycholic acid (TUDCA) on nerve function after acute spinal cord injury (SCI) in rats, observe its effect on neuronal apoptosis and caspase-12 expression levels, and investigate the underlying mechanism.. We used a modified Allen's weight-drop trauma method to establish a rat acute SCI model. The rats were randomly divided into three groups: group A (sham surgery group), group B (DMSO control group) and group C (TUDCA treatment group), with 36 rats in each group. At one minute and at 24 hours after successfully establishing the model, rats in group C received an intraperitoneal injection of TUDCA (200 mg/kg), while rats in group B received an equal amount of DMSO at the same time points. At 24 hours, three days, and five days after injury, a modified Tarlov scoring method and Rivlin's oblique plate test were used to evaluate rat spinal cord nerve function recovery. Animals were sacrificed at 24 hours, three days, and five days after injury. Specimens were obtained from the center of the injury sites; the pathological changes in spinal cord tissue were observed after hematoxylin-eosin (HE) staining; apoptosis was detected using the TUNEL method, and the expression of caspase-12 was measured at the protein level using immunohistochemistry and Western blots.. Group C differed significantly from group B in Tarlov scores and the oblique table test as early as 24 hours after the injury (P < 0.05). The TUNEL assay test results showed that neurons underwent apoptosis after SCI, which peaked at 24 hours. The ratios of apoptotic cells in group C were significantly lower than those in group B at 24 hours, three days, and five days after injury (P < 0.01). The immunohistochemistry and Western blot results showed that the caspase-12 expression levels of group C were lower than those of group B at 24 hours, three days, and five days after injury (P < 0.05).. TUDCA can inhibit the expression of caspase-12 in rat neurons after SCI, reduce cell apoptosis, and exert neuroprotective effects on rat secondary nerve injuries after SCI.

Topics: Acute Disease; Animals; Behavior, Animal; Blotting, Western; Caspase 12; Disease Models, Animal; Immunohistochemistry; In Situ Nick-End Labeling; Male; Motor Activity; Neuroprotective Agents; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Taurochenodeoxycholic Acid; Time Factors

Greater clinical understanding of the pivotal role of apoptosis in spinal cord injury (SCI) has led to new and innovative apoptosis-based therapies for patients with an SCI. Tauroursodeoxycholic acid (TUDCA) is a biliary acid with antiapoptotic properties. To our knowledge, this is the first study in the English language to evaluate the therapeutic efficacy of TUDCA in an experimental model of SCI. Thirty rats were randomized into three groups (sham-operated, trauma only, and trauma plus TUDCA treatment) of 10 each. In groups 2 and 3, spinal cord trauma was produced at the T8-T10 level via the Allen weight drop technique. Rats in group 3 were treated with TUDCA (200 mg/kg intraperitoneal) 1 min after trauma. The rats were killed either 24 h or 5 days after injury. The neuroprotective effect of TUDCA on injured spinal cord tissue and the effects of that agent on the recovery of hind-limb function were assessed. The efficacy of treatment was evaluated with histopathologic examination and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) analysis. Histopathologic characteristics were analyzed by comparison of hematoxylin-and-eosin stained specimens. Neurologic evaluations were performed 24 h, 3 days, and 5 days after trauma. Hind-limb function was assessed with the inclined plane technique of Rivlin and Tator and the modified version of Tarlov's grading scale. Twenty-four hours after injury, there was a significantly higher number of apoptotic cells in the lesioned spinal cord group than in the sham-operated control group. Treatment of the rats with TUDCA significantly reduced the number of apoptotic cells (4.52+/-0.30 vs. 2.31+/-0.24 in group 2) and the degree of tissue injury. Histopathologic examination showed that group 3 rats had better spinal cord architecture compared with group 2 rats. Five days after injury, the mean inclined plane angles in groups 1, 2, and 3 were 65.50 degrees +/- 2.09, 42.00 degrees +/- 2.74, and 53.50 degrees +/- 1.36. Motor grading of the rats revealed a similar trend. These differences were statistically significant (p<0.05). The mechanism of neuroprotection in the treated rats, although not yet elucidated, may be related to the marked antiapoptotic properties of TUDCA. A therapeutic strategy using TUDCA may eventually lead to effective treatment of SCI without toxic effects in humans.

Topics: Animals; Apoptosis; Cholagogues and Choleretics; Disease Models, Animal; In Situ Nick-End Labeling; Random Allocation; Rats; Rats, Wistar; Recovery of Function; Spinal Cord Injuries; Statistics, Nonparametric; Taurochenodeoxycholic Acid; Time Factors