Treatment Options For Spinal Cord Injury Research Articles

Effects of Recombinant IL-13 Treatment on Gut Microbiota Composition and Functional Recovery after Hemisection Spinal Cord Injury in Mice.

In recent years, the gut-central nervous system axis has emerged as a key factor in the pathophysiology of spinal cord injury (SCI). Interleukin-13 (IL-13) has been shown to have anti-inflammatory and neuroprotective effects in SCI. The aim of this study was to investigate the changes in microbiota composition after hemisection injury and to determine whether systemic recombinant (r)IL-13 treatment could alter the gut microbiome, indirectly promoting functional recovery. The gut microbiota composition was determined by 16S rRNA gene sequencing, and correlations between gut microbiota alterations and functional recovery were assessed. Our results showed that there were no changes in alpha diversity between the groups before and after SCI, while PERMANOVA analysis for beta diversity showed significant differences in fecal microbial communities. Phylogenetic classification of bacterial families revealed a lower abundance of the Bacteroidales S24-7 group and a higher abundance of Lachnospiraceae and Lactobacillaceae in the post-SCI group. Systemic rIL-13 treatment improved functional recovery 28 days post-injury and microbiota analysis revealed increased relative abundance of Clostridiales vadin BB60 and Acetitomaculum and decreased Anaeroplasma, Ruminiclostridium_6, and Ruminococcus compared to controls. Functional assessment with PICRUSt showed that genes related to glyoxylate cycle and palmitoleate biosynthesis-I were the predominant signatures in the rIL-13-treated group, whereas sulfolactate degradation super pathway and formaldehyde assimilation-I were enriched in controls. In conclusion, our results indicate that rIL-13 treatment promotes changes in gut microbial communities and may thereby contribute indirectly to the improvement of functional recovery in mice, possibly having important implications for the development of novel treatment options for SCI.

FGF23 alleviates neuronal apoptosis and inflammation, and promotes locomotion recovery via activation of PI3K/AKT signalling in spinal cord injury.

Fibroblast growth factor 23 (FGF23) regulates neuronal morphology, synaptic growth and inflammation; however, its involvement in spinal cord injury (SCI) remains unclear. Therefore, the present study aimed to investigate the effect of FGF23 on neuronal apoptosis, inflammation and locomotion recovery, as well as its underlying mechanism in experimental SCI models. Primary rat neurons were stimulated with H2O2 to establish an in vitro model of SCI and were then transfected with an FGF23 overexpression (oeFGF23) or short hairpin RNA (shFGF23) adenovirus-associated virus and treated with or without LY294002 (a PI3K/AKT inhibitor). Subsequently, an SCI rat model was constructed, followed by treatment with oeFGF23, LY294002 or a combination of the two. FGF23 overexpression (oeFGF23 vs. oeNC) decreased the cell apoptotic rate and cleaved-caspase3 expression, but increased Bcl-2 expression in H2O2-stimulated neurons, whereas shFGF23 transfection (shFGF23 vs. shNC) exhibited the opposite effect (all P<0.05). Furthermore, FGF23 overexpression (oeFGF23 vs. oeNC) could activate the PI3K/AKT signalling pathway, whereas treatment with the PI3K/AKT inhibitor (LY294002) (oeFGF23 + LY294002 vs. LY294002) attenuated these effects in H2O2-stimulated neurons (all P<0.05). In SCI model rats, FGF23 overexpression (oeFGF23 vs. oeNC) reduced the laceration and inflammatory cell infiltration in injured tissue, decreased TNF-α and IL-1β levels, and improved locomotion recovery (all P<0.05); these effects were attenuated by additional administration of LY294002 (oeFGF23 + LY294002 vs. LY294002) (all P<0.05). In conclusion, FGF23 alleviated neuronal apoptosis and inflammation, and promoted locomotion recovery via activation of the PI3K/AKT signalling pathway in SCI, indicating its potential as a treatment option for SCI; however, further studies are warranted for validation.

Targeting autophagy process in center nervous trauma.

The central nervous system (CNS) is the primary regulator of physiological activity, and when CNS is compromised, its physical functions are affected. Spinal cord injury (SCI) and traumatic brain injury (TBI) are common trauma in CNS that are difficult to recover from, with a higher global disability and mortality rate. Autophagy is familiar to almost all researchers due to its role in regulating the degradation and recycling of cellular defective or incorrect proteins and toxic components, maintaining body balance and regulating cell health and function. Emerging evidence suggests it has a broad and long-lasting impact on pathophysiological process such as oxidative stress, inflammation, apoptosis, and angiogenesis, involving the alteration of autophagy marker expression and function recovery. Changes in autophagy level are considered a potential therapeutic strategy and have shown promising results in preclinical studies for neuroprotection following traumatic brain injury. However, the relationship between upward or downward autophagy and functional recovery following SCI or TBI is debatable. This article reviews the regulation and role of autophagy in repairing CNS trauma and the intervention effects of autophagy-targeted therapeutic agents to find more and better treatment options for SCI and TBI patients.

Using Network Pharmacology to Systematically Decipher the Potential Mechanisms of Jisuikang in the Treatment of Spinal Cord Injury.

Objective To identify the potential pharmacological targets of Jisuikang (JSK) for the treatment of spinal cord injury (SCI) using network pharmacology. Methods The bioactive compounds of JSK herbs and their corresponding potential SCI targets were obtained from three traditional Chinese medicine (TCM) databases. SCI-related therapeutic target genes were obtained from the Comparative Toxicogenomics Database and the GeneCards Database. The common target genes between the JSK compounds and SCI-related therapeutic targets were screened using GO/KEGG functional enrichment and protein-protein interaction (PPI) analyses to identify hub genes and their categories of biological function. Gene expression distribution and receiver operating characteristic curve (ROC) analyses were used to identify probable SCI-related target genes. Molecular docking was used to quantify molecular interactions between target genes and the bioactive compounds of JSK. Results A total of 183 JSK bioactive compounds and 197 target genes for the treatment of SCI were screened and assessed. The target genes were enriched primarily in drug metabolism and in inflammation-related biological processes. Ten genes with statistical significance were identified as therapeutic SCI-related target genes of JSK. Molecular docking experiments demonstrated that the proteins of these 10 genes docked with binding energies of less than −5 kcal/mol with the bioactive compounds in JSK. Conclusion This study showed that the anti-SCI effects of JSK may be mediated through numerous bioactive components, multiple gene targets, and inflammation-related pathways and provided potential novel targets for directed therapies for treating SCI. These results provide a foundation for further experimental investigations into treatment options for SCI.

Protective effect of brain-derived neurotrophic factor and neurotrophin-3 overexpression by adipose-derived stem cells combined with silk fibroin/chitosan scaffold in spinal cord injury

ABSTRACT Objectives: Spinal cord injury (SCI) is a most debilitating traumatic injury, and cytotherapy is a promising alternative treatment strategy. Here we investigated the effect and mechanism of adipose-derived stem/stromal cells (ASCs) with overexpressing brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) (BDNF-NT3) in combination with silk fibroin/chitosan scaffold (SFCS) in SCI. Methods: Female Sprague-Dawley rats were used as an SCI model. SFCS,SFCS and ASCs, or ASCs overexpressing NT3, BDNF, and BDNF-NT3 were implanted into SCI rats. Basso, Beattie, and Bresnahan score, pathological changes, and spinal cord tissue and nerve fiber morphology were observed and assayed. GAP-43, GFAP, and caspase-3 expression was determined using immunohistochemistry and western blotting. Results: Smoother spinal cords, less scar tissue, and lower inflammatory activity were found in the SFCS, SFCS and ASCs, ASCs with NT3, BDNF, and BDNF-NT3 overexpression treatment than in the untreated SCI rat groups. Increasing formation of nerve fibers was observed in the above groups in order. GAP-43 expression significantly increased, while GFAP and caspase-3 expression significantly decreased. These results indicated obvious alleviation in pathological changes and BDNF-NT3 overexpression in ASCs combined with SFCS treatment in SCI rats. Conclusion: Thus, BDNF-NT3 overexpression from ASCs with SFCS had synergistic neuroprotective effects on SCI and may be a treatment option for SCI.

Ureteroscopy in patients with spinal cord injury: outcomes from a spinal injury unit and a review of literature.

Spinal cord injury (SCI) patients are at increased risk of developing urolithiasis. Ureteroscopic management for stone disease in SCI patients is underreported. Endourologists face many challenges in the management of stone disease in SCI patients including decreased stone free rates (SFR), increased infection risk, increased complication rate, anatomical variation, increased comorbidity level and challenges to nursing care. We present our experience at a regional SCI centre. Retrospective data was collected from 2005-2017 from a single SCI unit for patients who underwent ureteroscopy for stone disease. A total of 21 patients underwent 41 procedures, 7 cases being a planned multi-stage approach. Bladder management included sheath catheter, urethral catheter, suprapubic catheter, intermittent self-catheterisation, mitrofanoff, and ileal conduit. Spinal cord level was cervical (71%) or thoracic (29%), with American Spinal Injury Association (ASIA) grade classification A (86%), C (9%) and D (5%). Median follow-up time for patients was 46 months. Average stone size was 27 mm (range, 5-59 mm) access was achieved 98% of patients, with an access sheath used in 63%. The SFR was 47% with a recurrence rate (RR) of 42%. The complication rate was 24% all being Clavien Dindo grade 2. Ureteroscopy in SCI can be challenging and careful multidisciplinary team planning for intervention is needed. Ureteroscopy offers a useful treatment option for SCI, however, is associated with a lower SFR and greater complication rate compared to that of the general population.

Modeling trans-spinal direct current stimulation for the modulation of the lumbar spinal motor pathways

Objective. Trans-spinal direct current stimulation (tsDCS) is a potential new technique for the treatment of spinal cord injury (SCI). TsDCS aims to facilitate plastic changes in the neural pathways of the spinal cord with a positive effect on SCI recovery. To establish tsDCS as a possible treatment option for SCI, it is essential to gain a better understanding of its cause and effects. We seek to understand the acute effect of tsDCS, including the generated electric field (EF) and its polarization effect on the spinal circuits, to determine a cellular target. We further ask how these findings can be interpreted to explain published experimental results. Approach. We use a realistic full body finite element volume conductor model to calculate the EF of a 2.5 mA direct current for three different electrode configurations. We apply the calculated electric field to realistic motoneuron models to investigate static changes in membrane resting potential. The results are combined with existing knowledge about the theoretical effect on a neuronal level and implemented into an existing lumbar spinal network model to simulate the resulting changes on a network level. Main results. Across electrode configurations, the maximum EF inside the spinal cord ranged from 0.47 V m−1 to 0.82 V m−1. Axon terminal polarization was identified to be the dominant cellular target. Also, differences in electrode placement have a large influence on axon terminal polarization. Comparison between the simulated acute effects and the electrophysiological long-term changes observed in human tsDCS studies suggest an inverse relationship between the two. Significance. We provide methods and knowledge for better understanding the effects of tsDCS and serve as a basis for a more targeted and optimized application of tsDCS.

P091 Modeling the effects of trans-spinal direct current stimulation on the lumbar spinal circuits

Introduction Trans-spinal direct current stimulation (tsDCS) is a potentially new technique for the treatment of Spinal Cord Injury (SCI). The technique aims to alter the response of the neural pathways in the spinal cord, which is hypothesized to have a positive effect on SCI recovery. To establish tsDCS as a possible treatment option for SCI, it is vital to develop a better understanding of its underlying mechanisms to be able to adjust the intervention to the needs of the patient. Objectives We seek to understand the acute polarization effect of tsDCS on the lumbar spinal circuits. Further the question is, if acute, field dependent changes in synaptic efficacy could be used to explain the short term effects reported in previous tsDCS studies. Materials & methods We use a realistic full body segmented finite element model to calculate the electric field inside the spinal cord for three different electrode configurations (DC, 2.5 mA). We apply the calculated electric field to a set of realistic neuron models to investigate changes in membrane resting potential within the neuron as well as afferent and efferent axon terminals. We further make use of a lumbar spinal network model (Cisi et al., 2008) to simulate experimental paradigms used in previous tsDCS studies, with varying synaptic conductivities. The simulation results are correlated with acute, field dependent changes in synaptic efficacy observed in vitro and compared to the effects obtained by other tsDCS studies to date. Results Across electrode configurations, the electric field inside the spinal cord ranged from ∼0.2 V/m to ∼0.6 V/m with a more dominant longitudinal field component (radial/longitudinal 1/3). Across all MN models, axon terminal polarization was dominant ( Conclusion Axon terminal polarization may be a primary contributor to the modulatory effects observed after lumbar tsDCS. However, these longer term effects are opposite to the simulated acute synaptic efficacy changes. This may lead to better methods for predicting the outcome of tsDCS.

Human embryonic stem cells in the treatment of patients with spinal cord injury.

Spinal cord injury (SCI) is a neurological condition which paralyses the patient below the level of injury and could occur due to damage, infection and tumors. Presently, there is no cure for SCI. The treatment options used for SCI include corticosteroid (methylprednisolone sodium succinate), surgical interventions, and physiotherapy and lowering of body temperature. The research on treatment options for SCI has been shifted to cell-based therapies. Use of human embryonic stem cells (hESCs) have been explored in animal models in which these cells have been found to hold a potential to repair and regenerate. We wanted to assess the safety and efficacy of hESCs in the treatment of patients with spinal cord injury. Five patients who were either paraplegic or quadriplegic were treated with hESC therapy. Following the treatment, all patients showed significant improvement in their sitting balance, control and sensation of bowel and bladder, power and movement of limbs (lower limbs and upper limbs). No adverse events were reported. In conclusion, hESC is safe and effective therapy for SCI.

New perspectives for the treatment options in spinal cord injury

Spinal cord injury (SCI) is a serious clinical disorder that leads to lifetime disability for which no suitable therapeutic agents are available so far. Further research is needed to understand the basic mechanisms of spinal cord pathology that results in permanent disability and poses a heavy burden on our society. In the past, a lot of effort was placed on improving functional outcome with the help of various therapeutic agents, however less attention has been paid on the development and propagation of spinal cord pathology over time. Thus, it is still unclear whether improvement of functional outcome is related to spinal cord pathology or vice versa. Few drugs are able to influence functional outcome without having any improvement on cord pathology. Some drugs, however, can lessen cord pathology but fail to influence the functional outcome. The goal of future treatment options for SCI is therefore to find suitable new drugs or a combination of existing drugs and to use various cellular transplants, neurotrophic factors, myelin-inhibiting factors, tissue engineering and nano-drug delivery to improve both the functional and the pathological outcome in the inured patient. This review deals with the key aspects of the latest treatments for SCI and suggests some possible future therapeutic measures to enhance healthcare in clinical situations.