The Protein Kinase Inhibitor Midostaurin Improves Functional Neurological Recovery and Attenuates Inflammatory Changes Following Traumatic Cervical Spinal Cord Injury.
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ABSTRACT:
SUBMITTER: Zavvarian MM
PROVIDER: S-EPMC8301989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cervical spinal cord injury (SCI) leads to impaired trunk motor control, negatively impacting the performance of activities of daily living in the affected individuals. Improved trunk control with better sitting posture has been previously observed due to neuromuscular electrical stimulation and transcutaneous spinal stimulation, while improved postural stability has been observed with spinal cord epidural stimulation (scES). Hence, we studied how trunk-specific scES impacts sitting independence and posture. Fourteen individuals with chronic, severe cervical SCI with an implanted neurostimulator performed a 5-min tall-sit task without and with trunk-specific scES. Spine posture was assessed by placing markers on five spine levels and evaluating vertical spine inclination angles. Duration of trunk manual assistance was used to assess independence along with the number of independence changes and average independence score across those changes. With scES, the sacrum-L1 inclination and number of independence changes tended to decrease by 1.64 ± 3.16° (p = 0.07; Cohen's d = 0.53) and 9.86 ± 16.8 (p = 0.047; Cohen's d = 0.59), respectively. Additionally, for the participants who had poor sitting independence without scES, level of independence tended to increase by 12.91% [0%, 31.52%] (p = 0.38; Cohen's d = 0.96) when scES was present. Hence, trunk-specific scES promoted improvements in lower spine posture and lower levels of trunk assistance.
| S-EPMC10525621 | biostudies-literature
Project description:The objective of this study was to analyze the factors affecting the instant recovery of neurological function in patients with motor complete traumatic spinal cord injury (TSCI) treated in hospital. Methods: A retrospective analysis of 1053 patients with TSCI classified according to the American Spinal Cord Injury Association (ASIA) as grades A and B at 59 tertiary hospitals from 1 January 2018 to 31 December 2018 was performed. All patients were classified into motor complete injury (ASIA A or B) and motor incomplete injury (ASIA C or D) groups, according to the ASIA upon discharge. The injury level, fracture segment, fracture type, ASIA score at admission and discharge, treatment protocol, and complications were recorded. Univariate and multivariate analyses were performed to evaluate the relationship between various factors and the recovery of neurological function. Results: The results of multiple logistic regression analysis revealed that the ASIA score on admission (p < 0.001, odds ratio (OR) = 5.722, 95% confidence interval (CI): 4.147-7.895), fracture or dislocation (p = 0.001, OR = 0.523, 95% CI: 0.357-0.767), treatment protocol (p < 0.001; OR = 2.664, 95% CI: 1.689-4.203), and inpatient rehabilitation (p < 0.001, OR = 2.089, 95% CI: 1.501-2.909) were independently associated with the recovery of neurological function. Conclusion: The recovery of neurological function is dependent on the ASIA score on admission, fracture or dislocation, treatment protocol, and inpatient rehabilitation.
| S-EPMC9319428 | biostudies-literature
Project description:Previous studies suggest locomotion training could be an effective non-invasive therapy after spinal cord injury (SCI) using primarily acute thoracic injuries. However, the majority of SCI patients have chronic cervical injuries. Regaining hand function could significantly increase their quality of life. In this study, we used a clinically relevant chronic cervical contusion to study the therapeutic efficacy of rehabilitation in forelimb functional recovery. Nude rats received a moderate C5 unilateral contusive injury and were then divided into two groups with or without Modified Montoya Staircase (MMS) rehabilitation. For the rehabilitation group, rats were trained 5 days a week starting at 8 weeks post-injury (PI) for 6 weeks. All rats were assessed for skilled forelimb functions with MMS test weekly and for untrained gross forelimb locomotion with grooming and horizontal ladder (HL) tests biweekly. Our results showed that MMS rehabilitation significantly increased the number of pellets taken at 13 and 14 weeks PI and the accuracy rates at 12 to 14 weeks PI. However, there were no significant differences in the grooming scores or the percentage of HL missteps at any time point. Histological analyses revealed that MMS rehabilitation significantly increased the number of serotonergic fibers and the amount of presynaptic terminals around motor neurons in the cervical ventral horns caudal to the injury and reduced glial fibrillary acidic protein (GFAP)-immunoreactive astrogliosis in spinal cords caudal to the lesion. This study shows that MMS rehabilitation can modify the injury environment, promote axonal sprouting and synaptic plasticity, and importantly, improve reaching and grasping functions in the forelimb, supporting the therapeutic potential of task-specific rehabilitation for functional recovery after chronic SCI.
| S-EPMC7266985 | biostudies-literature
Project description:Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase, followed by partial self-recovery, and ultimately an equilibrium state of neurological dysfunction. Ferroptosis is a crucial pathological process in many neurodegenerative diseases; however, its role in chronic compressive spinal cord injury remains unclear. In this study, we established a chronic compressive spinal cord injury rat model, which displayed its most severe behavioral and electrophysiological dysfunction at 4 weeks and partial recovery at 8 weeks after compression. Bulk RNA sequencing data identified enriched functional pathways, including ferroptosis, presynapse, and postsynaptic membrane activity at both 4 and 8 weeks following chronic compressive spinal cord injury. Transmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression. Ferroptosis activity was negatively correlated with behavioral score. Immunofluorescence, quantitative polymerase chain reaction, and western blotting showed that expression of the anti-ferroptosis molecules, glutathione peroxidase 4 (GPX4) and MAF BZIP transcription factor G (MafG), in neurons was suppressed at 4 weeks and upregulated at 8 weeks following spinal cord compression. There was a positive correlation between the expression of these two molecules, suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury. In conclusion, our study determined the genome-wide expression profile and ferroptosis activity of a consistently compressed spinal cord at different time points. The results showed that anti-ferroptosis genes, specifically GPX4 and MafG, may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury. These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy.
| S-EPMC10360078 | biostudies-literature
Project description:Spinal cord injury (SCI) is a severe neurological disease; however, few drugs have been proved to treat SCI effectively. Neuroinflammation is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Salidroside (Sal) has been reported to exert anti-inflammatory effects in airway, adipose and myocardial tissue; however, the role of Sal in SCI therapeutics has not been clarified. In this study, we showed that Sal could improve the functional recovery of spinal cord in rats as revealed by increased BBB locomotor rating scale, angle of incline, and decreased cavity of spinal cord injury and apoptosis of neurons in vivo. Immunofluorescence double staining of microglia marker and M1/M2 marker demonstrated that Sal could suppress M1 microglia polarization and activate M2 microglia polarization in vivo. To verify how Sal exerts its effects on microglia polarization and neuron protection, we performed the mechanism study in vitro in microglia cell line BV-2 and neuron cell line PC12. The results showed that Sal prevents apoptosis of PC12 cells in coculture with LPS-induced M1 BV-2 microglia, also the inflammatory secretion phenotype of M1 BV-2 microglia was suppressed by Sal, and further studies demonstrated that autophagic flux regulation through AMPK/mTOR pathway was involved in Sal regulated microglia polarization after SCI. Overall, our study illustrated that Sal could promote spinal cord injury functional recovery in rats, and the mechanism may relate to its microglia polarization modulation through AMPK-/mTOR-mediated autophagic flux stimulation.
| S-EPMC5783886 | biostudies-other
Project description:BACKGROUND:Survival and therapeutic actions of bone marrow-derived mesenchymal stem cells (BMMSCs) can be limited by the hostile microenvironment present during acute spinal cord injury (SCI). Here, we investigated whether BMMSCs overexpressing insulin-like growth factor 1 (IGF-1), a cytokine involved in neural development and injury repair, improved the therapeutic effects of BMMSCs in SCI. METHODS:Using a SCI contusion model in C57Bl/6 mice, we transplanted IGF-1 overexpressing or wild-type BMMSCs into the lesion site following SCI and evaluated cell survival, proliferation, immunomodulation, oxidative stress, myelination, and functional outcomes. RESULTS:BMMSC-IGF1 transplantation was associated with increased cell survival and recruitment of endogenous neural progenitor cells compared to BMMSC- or saline-treated controls. Modulation of gene expression of pro- and anti-inflammatory mediators was observed after BMMSC-IGF1 and compared to saline- and BMMSC-treated mice. Treatment with BMMSC-IGF1 restored spinal cord redox homeostasis by upregulating antioxidant defense genes. BMMSC-IGF1 protected against SCI-induced myelin loss, showing more compact myelin 28 days after SCI. Functional analyses demonstrated significant gains in BMS score and gait analysis in BMMSC-IGF1, compared to BMMSC or saline treatment. CONCLUSIONS:Overexpression of IGF-1 in BMMSC resulted in increased cell survival, immunomodulation, myelination, and functional improvements, suggesting that IGF-1 facilitates the regenerative actions of BMMSC in acute SCI.
| S-EPMC6530133 | biostudies-literature
Project description:Study designMonocenter case-control study.ObjectiveEffects of spinal surgical adverse events (SSAE) on clinical and functional outcome, length of stay, and treatment costs after traumatic cervical spinal cord injury (SCI).Summary of background dataTraumatic SCI is a challenge for primary care centers because of the emergency setting and complex injury patterns. SSAE rates of up to 15% are reported for spine fractures without SCI. Little is known about SSAE after traumatic SCI and their outcome relevance.MethodsAcute traumatic cervical SCI patients were enrolled from 2011 to 2017. Cases with and without SSAE were compared regarding neurological recovery, functional outcome, secondary complications, mortality, length of stay, and treatment costs. Adjusted logistic regression and generalized estimating equation models were calculated for the endpoints ASIA impairment scale (AIS)-conversion and dysphagia. All analyses were run in the total and in a propensity score matched sample.ResultsAt least one SSAE occurred in 37 of 165 patients (22.4%). Mechanical instability and insufficient spinal decompression were the most frequent SSAE with 13 (7.9%) or 11 (6.7%) cases, respectively. The regression models adjusted for demographic, injury, and surgery characteristics demonstrated a reduced probability for AIS-conversion related to SSAE (OR [95% CI] 0.14 [0.03-0.74]) and additionally to single-sided ventral or dorsal surgical approach (0.12 [0.02-0.69]) in the matched sample. Furthermore, SSAE were associated with higher risk for dysphagia in the matched (4.77 [1.31-17.38]) and the total sample (5.96 [2.07-17.18]). Primary care costs were higher in cases with SSAE (median (interquartile range) 97,300 [78,200-112,300]) EUR compared with cases without SSAE (52,300 [26,700-91,200]) EUR.ConclusionSSAE are an important risk factor after acute traumatic cervical SCI with impact on neurological recovery, functional outcome, and healthcare costs. Reducing SSAE is a viable means to protect the limited intrinsic capacity for recovery from SCI.Level of Evidence: 4.
| S-EPMC8654254 | biostudies-literature
Project description:Mitochondrial dysfunction is a hallmark of secondary neuroinflammatory responses and neuronal death in spinal cord injury (SCI). Even though mitochondria-based therapy is an attractive therapeutic option for SCI, the efficacy of transplantation of allogeneic mitochondria in the treatment of SCI remains unclear. Herein, we determined the therapeutic effects of mitochondrial transplantation in the traumatic SCI rats. Compressive SCI was induced by applying an aneurysm clip on the T10 spinal cord of rats. A 100-μg bolus of soleus-derived allogeneic mitochondria labeled with fluorescent tracker was transplanted into the injured spinal cords. The results showed that the transplanted mitochondria were detectable in the injured spinal cord up to 28 days after treatment. The rats which received mitochondrial transplantation exhibited better recovery of locomotor and sensory functions than those who did not. Both the expression of dynamin-related protein 1 and severity of demyelination in the injured cord were reduced in the mitochondrial transplanted groups. Mitochondrial transplantation also alleviated SCI-induced cellular apoptosis and inflammation responses. These findings suggest that transplantation of allogeneic mitochondria at the early stage of SCI reduces mitochondrial fragmentation, neuroapoptosis, neuroinflammation, and generation of oxidative stress, thus leading to improved functional recovery following traumatic SCI.
| S-EPMC9039257 | biostudies-literature
Project description:Excessive inflammation post-traumatic spinal cord injury (SCI) induces microglial activation, which leads to prolonged neurological dysfunction. However, the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood. Ruxolitinib (RUX), a selective inhibitor of JAK1/2, was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung. However, its role in disrupting inflammation post-SCI has not been confirmed. In this study, microglia were treated with RUX for 24 hours and then activated with interferon-γ for 6 hours. The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited, and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cell proliferation marker Ki67 were reduced. In further in vivo experiments, a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days, and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway. Moreover, microglia treated with RUX centripetally migrated toward injured foci, remaining limited and compacted within the glial scar, which resulted in axon preservation and less demyelination. Moreover, the protein expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were reduced. The neuromotor function of SCI mice also recovered. These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway, thereby reducing secondary injury after SCI and producing neuroprotective effects.
| S-EPMC8848590 | biostudies-literature
Project description:Secondary damage following primary spinal cord injury extends pathology beyond the site of initial trauma, and effective management is imperative for maximizing anatomical and functional recovery. Bisperoxovanadium compounds have proven neuroprotective effects in several central nervous system injury/disease models, however, no mechanism has been linked to such neuroprotection from bisperoxovanadium treatment following spinal trauma. The goal of this study was to assess acute bisperoxovanadium treatment effects on neuroprotection and functional recovery following cervical unilateral contusive spinal cord injury, and investigate a potential mechanism of the compound's action. Two experimental groups of rats were established to 1) assess twice-daily 7 day treatment of the compound, potassium bisperoxo (picolinato) vanadium, on long-term recovery of skilled forelimb activity using a novel food manipulation test, and neuroprotection 6 weeks following injury and 2) elucidate an acute mechanistic link for the action of the drug post-injury. Immunofluorescence and Western blotting were performed to assess cellular signaling 1 day following SCI, and histochemistry and forelimb functional analysis were utilized to assess neuroprotection and recovery 6 weeks after injury. Bisperoxovanadium promoted significant neuroprotection through reduced motorneuron death, increased tissue sparing, and minimized cavity formation in rats. Enhanced forelimb functional ability during a treat-eating assessment was also observed. Additionally, bisperoxovanadium significantly enhanced downstream Akt and mammalian target of rapamycin signaling and reduced autophagic activity, suggesting inhibition of the phosphatase and tensin homologue deleted on chromosome ten as a potential mechanism of bisperoxovanadium action following traumatic spinal cord injury. Overall, this study demonstrates the efficacy of a clinically applicable pharmacological therapy for rapid initiation of neuroprotection post-spinal cord injury, and sheds light on the signaling involved in its action.
| S-EPMC3254642 | biostudies-literature