Treatment Of Traumatic Spinal Cord Injury Research Articles

Changing trends in traumatic spinal cord injury in an aging society: Epidemiology of 1152 cases over 15 years from a single center in Japan.

Traumatic spinal cord injury (TSCI) causes an insult to the central nervous system, often resulting in devastating temporary or permanent neurological impairment and disability, which places a substantial financial burden on the health-care system. This study aimed to clarify the up-to-date epidemiology and demographics of patients with TSCI treated at the largest SCI center in Japan. Data on all patients admitted to the Spinal Injuries Center with TSCI between May 2005 and December 2021 were prospectively collected using a customized, locally designed SCI database named the Japan Single Center Study for Spinal Cord Injury Database (JSSCI-DB). A total of 1152 patients were identified from the database. The study period was divided into the four- or five-year periods of 2005-2009, 2010-2013, 2014-2017, and 2018-2021 to facilitate the observation of general trends over time. Our results revealed a statistically significant increasing trend in age at injury. Since 2014, the average age of injury has increased to exceed 60 years. The most frequent spinal level affected by the injury was high cervical (C1-C4: 45.8%), followed by low cervical (C5-C8: 26.4%). Incomplete tetraplegia was the most common cause or etiology category of TSCI, accounting for 48.4% of cases. As the number of injuries among the elderly has increased, the injury mechanisms have shifted from high-fall trauma and traffic accidents to falls on level surfaces and downstairs. Incomplete tetraplegia in the elderly due to upper cervical TSCI has also increased over time. The percentage of injured patients with an etiology linked to alcohol use ranged from 13.2% (2005-2008) to 19% (2014-2017). Given that Japan has one of the highest aging populations in the world, epidemiological studies in this country will be very helpful in determining health insurance and medical costs and deciding strategies for the prevention and treatment of TSCI in future aging populations worldwide.

Bone Marrow Mesenchymal Stem Cells (BMSCs) Expressing Netrin-1 Alleviates Spinal Cord Injury (SCI)-Induced Inflammation

Spinal cord injury (SCI) is a common central nervous system (CNS) injury. Bone marrow mesenchymal stem cells (BMSCs) transplantation is a potential treatment for traumatic SCI. However, the role and mechanism of BMSCs with high expression of Netrin-1 on the repair and inflammation of spinal cord injury cells remains unclear. Our study intends to assess the effect of BMSCs with high Netrin-1 level on the repair of SCI cells. BMSCs or Netrin-1 transfected BMSCs were co-cultured with mechanically injured nerve cells followed by analysis of the differentiation of BMSCs by light microscope, apoptosis activity, expression of TLR-4 and NF-κB, and the TNF-α and IL-1β content in cell supernatant by ELISA. BMSCs with high Netrin-1 expression promoted the proliferation of BMSCs, inhibited apoptosis, and promoted the differentiation of nerve cells along with increased ALK activity, and the expression of GFAP and BDNF. Co-culture with BMSCs or BMSCs with high Netrin-1 expression increased mechanically damaged nerve cell proliferation, decreased apoptosis, downregulated TLR-4 and NF-κB (P < 0.05) with more significant changes after co-culture with BMSCs with high Netrin-1 expression. In conclusion, Netrin-1 can promote BMSCs proliferation and differentiation, and inhibit apoptosis. By inhibiting inflammation, it can promote damaged nerve cell proliferation and repair.

Exosome-Shuttled miR-672-5p from Anti-Inflammatory Microglia Repair Traumatic Spinal Cord Injury by Inhibiting AIM2/ASC/Caspase-1 Signaling Pathway Mediated Neuronal Pyroptosis.

Traumatic spinal cord injury (TSCI) is a devastating traumatic disease of the central nervous system, which leads to refractory loss of motor and sensory function. So far, there is no effective treatment for TSCI. Recently, however, nano-sized exosomes from various spinal cord cells have shown great prospects in the treatment of various diseases, including TSCI. Microglia are one of the components of the spinal cord microenvironment. Anti-inflammatory microglia (M2) have been shown to inhibit inflammation and promote the functional recovery of spinal cord after TSCI. However, the role micro RNAs (miRNAs) in exosomes derived from M2 microglia in the treatment of TSCI is unclear. In this study, we investigated whether M2 microglial exosomes (M2-Exos) could better promote the functional behavior recovery of mice with TSCI than M0 microglial exosomes (Exos). Compared with Exos, M2-Exos were found to have a better effect in promoting the recovery of functional behavior, promoting axon regeneration and reducing the level of pyroptosis of spinal cord neurons after TSCI. Through a series of experiments, we also confirmed that miR-672-5p is the most critical miRNA associated with M2-Exos, and that its targeting gene is AIM2. M2-Exos rich in miR-672-5p could inhibit the AIM2/ASC/caspase-1 signaling pathway by inhibiting AIM2 activity, so as to inhibit neuronal pyroptosis and finally promote the recovery of functional behavior in mice with TSCI. In conclusion, our study suggests that the application of M2-Exos may be a promising treatment strategy for TSCI.

Actualización en la fisiopatología y manejo de traumatismo raquimedular. Revisión bibliográfica

El Traumatismo Raquimedular (TRM) implica todas las lesiones traumáticas que dañan los huesos, ligamentos, músculos, cartílagos, estructuras vasculares, radiculares o meníngeas a cualquier nivel de la médula espinal. Las consecuencias personales, familiares, sociales y económicas de esta enfermedad, hacen que sea un tema relevante en la actualidad. El propósito de esta revisión es entregar al lector las herramientas elementales sobre el TRM, y está principalmente enfocada en el tratamiento, el cual se aborda estrechamente relacionado con la fisiopatología para comprender los mecanismos moleculares y biomecánicos de trauma, incluyendo sus complicaciones y el manejo de éstas. Respecto al tratamiento del TRM, se aborda la evidencia que ofrecen las terapias actualmente validadas y las aún controversiales, incluyendo los glucocorticoides, la reducción cerrada y la cirugía precoz. Además las terapias emergentes como la hipotermia terapéutica, los nuevos agentes neuroprotectores que se encuentran en fases preclínicas y clínicas de estudio como el riluzol, la minociclina, el litio, los antagonistas opioides, entre otros, y los agentes neurorregenerativos como el Cethrin y el Anti-Nogo que han mostrado buenos resultados en la recuperación neurológica. Las recomendaciones actuales respecto a la terapia con células madre y subtipos de células madre en la actualidad, es que deben llevarse a cabo sólo en el contexto de ensayos clínicos. Aunque aún no existen terapias que permitan la recuperación neurológica completa en todos o la mayoría de los pacientes, las terapias emergentes prevén un futuro promisorio en los resultados clínicos de los pacientes con TRM.

Necrosulfonamide Attenuates Spinal Cord Injury via Necroptosis Inhibition

Spinal cord injury (SCI) is a serious trauma without efficient treatment currently. Necroptosis can be blocked post injury by special inhibitors. This study is to investigate the effects, mechanism, and potential benefit of necrosulfonamide (NSA) for SCI therapy. Pathologic condition was detected using hematoxylin-eosin staining on injured spinal cord and other major organs. Necroptosis-related factors-RIP1, RIP3, and MLKL-were detected using Western blot. Detections on mitochondrial functions such as adenosine triphosphate generation and activities of superoxide dismutase and caspase-3 were also performed. Finally, ethologic performance was detected using a 21-point open-field locomotion test. Reduced lesions and protected neurons were found in the injured spinal cord after treatment with NSA using hematoxylin-eosin staining for pathologic detection. No obvious toxicity on rat liver, kidney, heart, and spleen was detected. Rather than RIP1 and RIP3, MLKL was significantly inhibited by the NSA using Western blot detection. Adenosine triphosphate generation was obviously decreased post injury but slightly increased after the NSA treatment, especially 24 hours post injury. No significant changes were found on activities of superoxide dismutase and caspase-3 after the treatment of NSA. Ethologic performance was significantly improved using a 21-point, open-field locomotion test. Our research indicates NSA attenuates the spinal cord injury via necroptosis inhibition. It might be a potential and safe chemical benefit for SCI therapy. To our knowledge, this is the first study on the effects of NSA as treatment of traumatic SCI.

The Cell Therapy in Traumatic Spinal Cord Injury

The opportunities and the most promising ways of using cellular technology in traumatic spinal cord injury are considered in this review. A large number of experimental and clinical studies with the use of different types of cells: embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, Schwann cells, olfactory mucosa cells, and others – was conducted. The use of these types of cells in traumatic spinal cord injury treatment often demonstrated a positive therapeutic effect: the motor and sensory function recovery of the spinal cord. However, some types of cell preparations involve some methodological and ethical problems; some types of cell therapies are ineffective or give rise to side effects. These factors complicate the selection of optimal cell therapy for the traumatic spinal cord injury treatment. The most promising cells seem to be the cells of the olfactory mucosa. Getting the olfactory mucosa is considered to be a feasible and safe procedure for patients. The clinical application of the cells of the olfactory mucosa is effective in motor function recovery due to remyelination and axonal regeneration after spinal cord injury. These cells are tissue-specific and autologous since they can be obtained from a patient with spinal cord injury, and after cultivation, expansion, and directed differentiation they can be transplanted to the same patient. The presented benefits of olfactory mucosa cells open up the possibility for its clinical application in the cell therapy.

Diadenosine tetraphosphate (Ap4A) inhibits ATP-induced excitotoxicity: a neuroprotective strategy for traumatic spinal cord injury treatment.

Reducing cell death during the secondary injury is a major priority in the development of a cure for traumatic spinal cord injury (SCI). One of the earliest processes that follow SCI is the excitotoxicity resulting from the massive release of excitotoxicity mediators, including ATP, which induce an excessive and/or prolonged activation of their receptors and a deregulation of the calcium homeostasis. Diadenosine tetraphosphate (Ap4A) is an endogenous purinergic agonist, present in both extracellular and intracellular fluids, with promising cytoprotective effects in different diseases including neurodegenerative processes. In a search for efficient neuroprotective strategies for SCI, we have tested the capability of Ap4A to reduce the excitotoxic death mediated by the ATP-induced deregulation of calcium homeostasis and its consequences on tissue preservation and functional recovery in a mouse model of moderate contusive SCI. Our analyses with the murine neural cell line Neuro2a demonstrate that treatment with Ap4A reduces ATP-dependent excitotoxic death by both lowering the intracellular calcium response and decreasing the expression of specific purinergic receptors. Follow-up analyses in a mouse model of contusive SCI showed that acute administration of Ap4A following SCI reduces tissue damage and improves motor function recovery. These results suggest that Ap4A cytoprotection results from a decrease of the purinergic tone preventing the effects of a massive release of ATP after SCI, probably together with a direct induction of anti-apoptotic and pro-survival pathways via activation of P2Y2 proposed in previous studies. In conclusion, Ap4A may be a good candidate for an SCI therapy, particularly to reduce excitotoxicity in combination with other modulators and/or inhibitors of the excitotoxic process that are being tested.

The role of specialist units to provide focused care and complication avoidance following traumatic spinal cord injury: a systematic review.

Current recommendations for traumatic spinal cord injury treatment recommend immediate transfer to a spinal injury unit (SIU) where available following patient stabilisation. Although transfer is dependent on a variety of factors, the largest review was unable to justify implementation of such units on the basis of insufficient and lack of quality data in favour of care at the SIU as opposed to non-SIU centres. Our study sought to investigate: are subspecialty spinal injury units (SIUs) able to provide superior care compared with traditional trauma/rehab units? Is the standard of care of acute spinal cord injured patients to be managed in SIU's? A literature search was conducted across five major databases using the key terms: "spinal cord injury" AND "Spinal Injury Unit" OR "spinal rehabilitation" OR "spinal injury centre" OR "specialist care" OR "care requirements." After review of over 500 studies, only 9 met inclusion criteria, 3 of which were past reviews. There were no relevant RCT's obtained. Standardised roles of global SIU units are needed to deliver equitable and high quality care as current evidence demonstrates variable standards of care and service (mean LOS range: 16-174days). There is low quality evidence supporting earlier admission into SIU units being associated with improved neurological outcome, complication rates and reduced LOS, despite variations in the definition of "early admission" across studies. Our review demonstrates a lack of standardisation within SIU on a global scale, with significantly different outcomes reported across published studies. New and higher quality evidence directly comparing SIU to non-SIU based care is required. Earlier transfer (<24h) to SIU following initial injury and stabilisation is advised.

Effect of Asiatic Acid on the Treatment of Spinal Cord Injury: An Experimental Study in Rats.

Spinal cord injury (SCI) is a devastating condition of the central nervous system. There is no proven therapeutic agent for the treatment of this complex disorder. Asiatic acid (AA) has been used as an anti-inflammatory and anti-oxidant agent in Eastern countries for many years. The aim of this study was to investigate the effectiveness of AA on the treatment of traumatic SCI in rats. Thirty-two adult male Sprague-Dawley rats were divided into 4 groups as laminectomy, laminectomy+trauma, vehicle, and AA treatment groups. SCI was created by the modified Allen"s weight-drop technique. After the injury, the levels of pro-inflammatory cytokines (IL-6, IL1-&Beta;, TNF-&alpha;) and lipid peroxidation products (MDA) were measured. Tarlov functional recovery scores were also determined for each rat. The One-way ANOVA test was used for the analysis of difference between 4 experimental groups and the groups were compared individually by Tukey-LSD post hoc analysis test (p=0.001). AA administration just after SCI attenuated the levels of lipid peroxidation products (MDA) and pro-inflammatory cytokines (TNF-&alpha;, IL1&Beta;). It also increased the Tarlov functional recovery scores of the rats. AA administration could attenuate a number of deleterious reactions after traumatic SCI. Further studies are needed to elucidate the pathways of neuroprotective effects of AA after spinal trauma.

Necroptosis inhibitor necrostatin-1 promotes cell protection and physiological function in traumatic spinal cord injury

Spinal cord injury (SCI) is a common and serious trauma which lacks efficient treatment. Inhibition of cell death in the trauma area is important for spinal cord protection during this process. In this study, necroptosis inhibitor necrostatin-1 (Nec-1) was used to treat SCI rats, to investigate the role of Nec-1 in the recovery of SCI. Nec-1 was found to reduce lesions, cytokines and reactive oxygen species (ROS), improve pathological conditions and blood supply in the spinal cord trauma area. Further study indicated that Nec-1 could inhibit necroptosis by inhibiting RIP1/3–MLKL recruitment and inhibit apoptosis by inhibiting Caspase 3 and Bax while activating Bcl-2. Ethological performance of SCI rats confirmed improvement and protection of physiological function by Nec-1. Nec-1 as a potential treatment for SCI warrants further study. To our knowledge, this is the first study on the role of Nec-1 in the treatment of traumatic SCI. Our research also found inhibition effects of Nec-1 on apoptosis, not only necroptosis – as reported by most publications.

FK506 Treatment Inhibits Caspase-3 Activation and Promotes Oligodendroglial Survival Following Traumatic Spinal Cord Injury

The focus of this study is to examine the ability of FK506, an immunosuppressant that inhibits calcineurin activation, to limit caspase-3 activation in oligodendroglia following spinal cord injury (SCI). To better establish a role for calcineurin and caspase-3 activation in oligodendroglia following SCI, rats received a contusion injury to the spinal cord followed by treatment with FK506 or rapamycin (another immunosuppressant with no detectable inhibitory action on calcineurin activation). Animals were then sacrificed at 8 days postinjury and spinal cord tissue was processed using immunofluorescence histochemistry to examine cellular caspase-3 activation in ventral and dorsal white matter. In all treatment groups, numerous oligodendroglia were found to express the activated form of caspase-3 in regions proximal and distal to the injury epicenter. However, our findings suggest that treatment with FK506, but not rapamycin reduces the number of oligodendroglia expressing activated caspase-3 and increases the number of surviving oligodendroglia in dorsal white matter. These results provide initial evidence that agents that reduce the actions of calcineurin and subsequent caspase-3 activation may prove beneficial in the treatment of traumatic SCI.

Therapeutic implications of fibroblast growth factors in traumatic spinal cord injury

Neurological damage after acute traumatic spinal cord injury (SCI) results from both the primary mechanical injury as well as the subsequent activation of cell death cascades mediating delayed tissue damage. Since secondary injury following traumatic SCI is a tightly regulated process in which several neurotrophic factors seem to be implicated, administration of these proteins has a clinical interest. Fibroblast growth factor may be one of the agents to be used for the treatment of traumatic SCI. [Neurol Res 2001; 23: 207-209]

Role of leukocytes in spinal cord injury in rats.

Spinal cord injury (SCI) is a serious condition that produces life-long disabilities. Only limited therapeutic measures are currently available for its treatment. This review describes the role of leukocytes in pathologic mechanisms of trauma-induced SCI in rats, which contributes to new understanding of the pathologic process involved in SCI and could lead to the development of new therapeutic strategies by which leukocyte activation can be regulated. SCI induced by trauma is a consequence of an initial physical insult that is followed by a progressive injury process which involves various pathochemical events that lead to tissue destruction. Therapeutic intervention in SCI should therefore be directed at reducing or alleviating this secondary process. Although the mechanisms are not fully understood, progressive vascular events, especially activated neutrophil-induced endothelial cell damage, have been shown to be implicated. We have found that some therapeutic agents, which inhibit leukocyte activation directly or indirectly, alleviate the motor disturbances observed in a rat model of SCI. Methylprednisolone (MPS) and GM1 ganglioside, which are the only two pharmacological agents currently clinically available for treatment of acute SCI, do not inhibit neutrophil activation in this rat model. Taken together, these observations raise a possibility that pharmacological agents that inhibit leukocyte activation used in conjunction with MPS or GM1 may have a synergistic effect in the clinical treatment of traumatic SCI in humans.