Spinal cord injury (SCI) is a devastating condition resulting from traumatic or nontraumatic injury/chronic disorder. The pathogenesis of SCI necessitates a comprehensive approach, as it involves therapeutic strategies addressing both bone (spine) and neural (spinal cord) damage. This review centers on the pivotal role of nitric oxide (NO) and its synthesizing enzymes, nitric oxide synthases (NOS), in mediating the crosstalk between osteogenesis and neurogenesis. NO's effects are context-dependent, exhibiting a delicate balance between beneficial and detrimental actions. Reduced levels of nitric oxide (NO), primarily derived from endothelial NOS (eNOS), tipically stimulate osteoblast activity and promote neurogenesis by influencing neural stem cell (NSC) migration and differentiation. Conversely, elevated NO levels, predominantly from inducible NOS (iNOS), tipically triggered by inflammation, inhibit both processes through pro-apoptotic mechanisms. Nevertheless, these phenomena are not merely simplistic; they can be influenced by a variety of other factors. We explore the intricate interplay of NO/NOS with key signaling pathways crucial in neurogenesis and osteogenesis, including mechanical stimuli, Wnt, interleukins, BMPs, NF-κB, etc., revealing their influence on neuroinflammation, neurogenesis, and osteoblast differentiation. The temporal and spatial dynamics of NO/NOS activity and the implications for therapeutic intervention have been discussed. Precise modulation of NO levels and NOS isoforms, potentially through targeted therapies manipulating these interacting signaling pathways, emerges as a promising strategy for promoting bone and neural regeneration. This review highlights the critical need for a balanced approach in therapeutic strategies to harness the beneficial effects of NO/NOS while mitigating its detrimental consequences.

Spinal cord injury (SCI) is a neurological disorder characterized by severe and often irreversible damage to the spinal cord, for which no effective treatments currently exist. Ubiquitination, a reversible post-translational modification, plays a critical role in regulating protein degradation and stabilization. Tripartite motif-containing 55 (TRIM55), an E3 ubiquitin ligase, belongs to the TRIM protein family. This study aimed to explore the potential mechanism of TRIM55 in SCI.

An SCI rat model was established to investigate the effects of TRIM55 on SCI. LPS-stimulated PC12 cells were used to evaluate inflammation by measuring IL-1β, IL-6, and TNF-α levels using enzyme-linked immunosorbent assays. The proliferation and apoptosis of PC12 cells were assessed using the cell counting kit-8 assay and TUNEL staining. Quantitative real-time PCR, western blot analysis, co-immunoprecipitation, and cycloheximide chase experiments were performed to elucidate the underlying mechanism.

The findings revealed that TRIM55 was downregulated both in vitro and in vivo. Functionally, TRIM55 inhibited apoptosis and reduced the expression of pro-inflammatory cytokines in LPS-stimulated PC12 cells. Mechanistically, TRIM55 interacted with toll-like receptor 4 (TLR4) and promoted its degradation by modulating the ubiquitination process, thereby attenuating the inflammatory response. Furthermore, TRIM55 enhanced recovery from SCI and alleviated inflammation in vivo.

This study not only provides robust theoretical evidence supporting TRIM55 as an anti-inflammatory factor but also offers a novel therapeutic approach for SCI research.

Neuroinflammation is a major driver of secondary tissue damage after spinal cord injury (SCI). Within minutes after SCI, activated microglia and astrocytes produce proinflammatory mediators such as TNF-α, IL-6, iNOS, and COX-2 which induce tissue injury through cytotoxicity, vascular hyperpermeability, and secondary ischemia. The inflammatory cascade is amplified by chemokines like CCL2 and CXCL1 which recruit immune cells to the injured site. HuR is an RNA regulator that promotes glial expression of many proinflammatory factors by binding to adenylate- and uridylate-rich elements in the 3' untranslated regions of their mRNAs. SRI-42127 is a small molecule which blocks HuR function by preventing its nucleocytoplasmic translocation. This study aimed to evaluate the potential of SRI-42127 to suppress neuroinflammation after SCI and improve functional outcome. Adult female mice underwent a T10 contusion injury and received SRI-42127 1 h post injury for up to 5 days. Locomotor function was assessed by open field testing, balance beam, and rotarod. Immunohistochemistry was used to assess lesion size, neuronal loss, myelin sparing, microglial/astroglial activation, and HuR localization. Inflammatory mediator expression was assessed by qPCR, immunohistochemistry, ELISA, or western blot. We found that SRI-42127 treatment significantly attenuated loss of locomotor function and post-SCI pain. There was a reduction in lesion size and neuronal loss with an increase in myelin sparing. Microglia and astrocytes showed reduced activation and reduced nucleocytoplasmic translocation of HuR. There was a striking suppression of proinflammatory mediators at the epicenter along with peripheral suppression of inflammatory responses in serum, liver, and spleen. In conclusion, HuR inhibition with SRI-42127 may be a viable therapeutic approach for suppressing neuroinflammatory responses after SCI and improving functional outcome.

Spinal cord injury (SCI) is a disability that causes severe traumatic damage to the central nervous system, with increasing prevalence worldwide. Paclitaxel (PTX) is a naturally occurring plant metabolite that has been shown to exhibit various neuroprotective effects in the central nervous system, however, the specific mechanisms underlying its protective effects in SCI remain unclear. In this study, we aimed to explore the therapeutic effects of PTX in SCI, as well as elucidate the underlying molecular mechanisms associated with its neuroprotective potential.

Murine models of spinal cord compression were performed followed by intrathecal administration of corresponding agents for 21 days. Mice were randomly divided into the following four groups: Sham, SCI + Saline, SCI + PTX, and SCI + PTX + XAV939. Recovery of lower limb function and strength, as well as muscular atrophy were examined via multiple scored tests. Degree of neuronal and axonal damage, as well as fibrosis were examined via immunohistochemical staining.

PTX administration significantly improved the recovery of lower limb function and strength, prevented muscular atrophy, as well as decreased the extent of neuronal and axonal death following SCI surgery. PTX also robustly activated the Wnt/β-catenin protein signaling pathway that played a key role in its therapeutic effects. Co-administration with a Wnt/β-catenin pathway inhibitor - XAV939, significantly abolished the beneficial effects of PTX after SCI.

This study provides important new mechanistic insight on the beneficial effects of PTX in protecting against spinal cord injury, as well as the experimental basis for its potential therapeutic use.

Bioinformatics analysis and experimental validation study.

To investigate the role and expression patterns of disulfidptosis-related genes in spinal cord injury (SCI), identify potential pivotal genes, and explore possible therapeutic targets.

Shanghai, China.

Data acquisition and pre-processing: Screened 27 disulfidptosis-related genes based on literature and downloaded RNA-sequencing data of ASCI patients from GEO database (GSE151371); Identification of differentially expressed genes (DEGs): Used R package "limma" for differential gene expression analysis between ASCI samples and normal controls; Evaluating immune cell infiltration: Employed ssGSEA algorithm and CIBERSORT to determine immune cell abundance; Identification and functional verification of key genes: Intersected disulfidptosis-related genes with DEGs, and used machine learning techniques (Random Forest, Lasso, Support Vector Machine) to identify hub genes. Validated hub genes expression by real-time PCR; Construction of a diagnostic model: Developed a backpropagation neural network clinical prediction model based on hub genes and clinical features, and evaluated its performance using ROC curve. 6. Subcluster analysis: Performed consensus cluster analysis of ASCI samples and hub genes, and used GSVA to elucidate functional differences between subgroups.

Identified 7764 DEGs in ASCI, with GO and KEGG enrichment in inflammation and autophagy-related pathways; Found differences in immune cell infiltration between ASCI and control groups, and correlation between immune cells and DRGs; Determined seven hub genes (MYL6, NUBPL, CYFIP1, IQGAP1, FLNB, SLC7A11, CD2AP) through machine learning; Validated the expression of hub genes by qRT-PCR; Constructed a clinical diagnostic model with good predictive accuracy (overall dataset accuracy of 83.3%); Identified two subtypes of ASCI based on hub genes, with different immune infiltration and pathway activity.

Disulfidptosis is closely related to spinal cord injury. The identified hub genes and subtypes provide new insights for biomarker and therapeutic target research. The diagnostic model has potential for clinical application, but further studies are needed due to limitations such as small sample size.

This study was supported in part by the project of Youth Scientific and Technological Talents of PLA (2020QN06125), Changhong Talent Project in First affiliated hospital of Navy Medical University (Wei Xianzhao) and Basic Medical Research Project in First affiliated hospital of Navy Medical University (2023PY17). I want to reiterate that there is no prior publication of figures or tables and no conflict of interest in the submission of this manuscript. The graphical abstract is divided into two parts. The upper section sequentially illustrates the occurrence of disulfidptosis and changes in the immune microenvironment in the human body after SCI. The lower section displays the construction of a diagnostic model for SCI through the detection of changes in disulfidptosis-related genes, combined with patient clinical information.

Spinal cord injury (SCI) constitutes a profound central nervous system disorder characterized by significant neurological dysfunction and sensory loss below the injury site. SCI elicits a multifaceted cellular response in which the proliferation of reactive astrocytes and the ensuing diversity in their functions and phenotypes play pivotal roles within the injury microenvironment, especially during the secondary phases of the condition. This review explores the activation and heterogeneity of astrocytes following SCI. It underscores the necessity of delineating the heterogeneity among reactive astrocyte subpopulations throughout the secondary injury phase of SCI. Developing therapeutic strategies that capitalize on the beneficial properties of certain reactive astrocyte subpopulations while mitigating the adverse effects of others could have profound implications for future clinical management of SCI.

BackgroundAccurate prognostic assessment of critically ill trauma patients in emergency departments is crucial for early intervention and improving survival rates. This study investigates the relationship between blood parameters, disease severity, and patient outcomes.ObjectiveTo explore the relationship between blood parameters and the severity and prognosis of critically ill trauma patients in an emergency trauma center. The goal is to facilitate early diagnosis, implement measures to improve survival rates, and enhance patient outcomes.MethodsThis retrospective study analyzed the blood parameters of 569 critically ill trauma patients admitted to the trauma center from 2020 to August 2023. The analysis focused on examining the relationship between these parameters and the severity and prognosis of the patients.ResultsCompared to the improved and non-recovered groups, the mortality group had longer times from injury to hospital admission, higher ISS and NEWS scores, lower GCS scores, more acidic blood gas analysis, electrolyte imbalances, and poorer liver and kidney function as well as coagulation indicators.ConclusionLow pH, high PaCO2, high lactate, high potassium, high NLR, high D-Dimer, high ISS, and high NEWS are independent risk factors. Conversely, high PLT, albumin, and GCS scores are independent protective factors. These indicators can effectively predict the prognosis of trauma patients.

Spinal cord injury (SCI) remains a profound medical challenge, with limited therapeutic options available. Studies focusing on individual molecular markers have limitations in addressing the complex disease process.

This study utilizes RNA-sequencing (RNA-seq) to investigate the differentially expressed genes (DEGs) in spinal cord tissue from a rat SCI model at 1 and 21 days post-injury (dpi). After data processing and analysis, a series of biological pathway enrichment analyses were performed using online tools DAVID and GSEA. Interactions among the enriched genes were studied using Cytoscape software to visualize protein-protein interaction networks.

Our analysis identified 595 DEGs, with 399 genes significantly upregulated and 196 significantly downregulated at both time points. CD68 was the most upregulated gene at 21 dpi, with a significant fold change at 1 dpi. Conversely, MPZ was the most downregulated gene. Key immune response processes, including tumor necrosis factor (TNF) production, phagocytosis, and complement cascades, as well as systemic lupus erythematosus (SLE)-associated pathways, were enriched in the upregulated group. The enriched pathways in the downregulated group were related to the myelin sheath and neuronal synapse. Genes of interest from the most significantly downregulated DEGs were SCD, DHCR24, PRX, HHIP, and ZDHHC22. Upregulation of Fc-γ receptor genes, including FCGR2B and FCGR2A, points to potential autoimmune mechanisms.

Our findings highlight complex immune and autoimmune responses that contribute to ongoing inflammation and tissue damage post-SCI, underscoring new avenues for therapeutic interventions targeting these molecular processes.

Spinal cord injury (SCI) is a critical neurological disorder that frequently leads to permanent disability, profoundly affecting the quality of life of individuals with SCI. In this research, we examined the varied expression of genes associated with metabolic reprogramming-related genes in SCI. By employing the Gene Expression Omnibus datasets GSE5296 and GSE47681, 1001 differentially expressed genes (DEGs) were identified through the limma R package. Among these, 871 and 130 genes were upregulated and downregulated, respectively. A subset of 10 metabolic reprogramming-related differentially expressed genes (MRRDEGs) was recognized as key players in metabolic reprogramming. Analyses of enrichment performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes indicated that the identified MRRDEGs predominantly participated in processes related to pyruvate metabolism and carbohydrate degradation. Nine hub genes were discerned using a protein-protein interaction network. Subsequently, an SCI mouse model was established using the LISA SCI modeling device, and preliminary validation was conducted through quantitative real-time PCR experiments at various time points after SCI, specifically on days 1, 3, and 7, suggesting their central role in SCI. Receiver operating characteristic curve analysis indicated that these MRRDEGs could be used to diagnose SCI. The CIBERSORT algorithm analysis of immune infiltration identified an inverse relationship between M0 and M2 macrophages. Furthermore, a positive relationship was observed between Ucp2 and M0 macrophages, underscoring their essential function in the immune response following SCI. These results highlight MRRDEGs' importance in SCI and propose their potential roles as targets for therapeutic interventions.

Spinal cord injury (SCI) affects millions of people worldwide annually, presenting significant challenges in functional recovery despite therapeutic advancements. Current treatment strategies predominantly focus on stabilizing the spinal cord and facilitating neural repair, yet their effectiveness remains uncertain and controversial. Recent scientific investigations have explored the potential of probiotics and postbiotics to modulate inflammation, influence neurotransmitters, and aid in tissue repair, marking a potential paradigm shift in SCI management. This review critically evaluates these innovative approaches, emphasizing their ability to harness the natural properties of microorganisms within the body to potentially enhance outcomes in SCI treatment. By analyzing the latest research findings, this review provides valuable insights into how probiotics and postbiotics can revolutionize inflammation management and neurological recovery following SCI, underscoring their promising role in future therapeutic strategies aimed at improving the quality of life of SCI patients globally.

Spinal cord injury (SCI) can cause irreversible nerve damage, imposing a significant burden on both patients and society. Methylprednisolone (MP), the recommended clinical drug, possesses antioxidant, anti-inflammatory, and antiapoptotic effects. It improves nerve damage by inhibiting secondary pathological processes. However, high-dose MP administration may result in side effects, including diabetes, femoral head necrosis, and infections. Therefore, there is a need to identify safer alternatives to mitigate the issues associated with MP administration. Rutin, a natural small molecule, exhibits multifaceted therapeutic capabilities and high biosafety, making it a promising alternative to MP treatment. However, its poor solubility and rapid metabolism limit its in vivo bioavailability. In this study, a drug-free polypeptide (PAH) containing hydrazide groups on the side chains is designed, which can be used for mitigating secondary SCI through scavenging toxic aldehydes. Then, we utilize PAH to encapsulate rutin and develop aldehyde-responsive nanomedicine for intravenous administration in SCI rats, providing a novel approach for the clinical replacement of MP.

Spinal cord injury (SCI) remains a devastating central nervous system disorder. The complex pathological microenvironment following SCI, particularly the imbalance in neuroinflammation, contributes to its therapeutic challenges. Microglial pyroptosis, a type of programmed cell death, is pivotal in exacerbating neuroinflammation and secondary tissue damage after SCI. Our previous study demonstrated the inhibitory efficacy of conditioned medium (CM) derived from human dental pulp stem cells (DPSCs) on the microglial pyroptosis and its positive effects on the functional recovery in SCI models. However, the major secretory product in CM responsible for inhibiting microglial pyroptosis remains unclear.

We aim to investigate whether vascular endothelial growth factor (VEGF) secreted by human DPSCs can alleviate microglial pyroptosis through the PI3K/AKT signaling pathway and promote motor and electrophysiological function recovery in SCI mice.

Human DPSCs were isolated and cultured, and CM was collected for VEGF detection and further treatment. The BV2 cell line was established as a microglial pyroptosis model through the administration of lipopolysaccharide (LPS). SCI was induced in mice. Molecular and histological techniques were employed to evaluate pyroptosis and explore the underlying mechanisms both in vivo and vitro.

Human DPSC-derived VEGF significantly inhibited microglial pyroptosis both in vitro and vivo, as evidenced by the decreased expression of pyroptosis-related markers, such as caspase-1 and IL-1β. The anti-pyroptotic effects of VEGF were closely associated with the activation of the PI3K/AKT signaling pathway, which was identified as a key regulatory mechanism. Importantly, treatment with DPSC-CM improved the recovery of motor function and electrophysiological conduction in SCI mice.

Human DPSC-derived VEGF alleviates microglial pyroptosis via the PI3K/AKT signaling pathway, thereby contributing to the repair of SCI. Our study provides new insights into the potential for therapy of DPSCs and their secreted factors, particularly VEGF, offering new perspectives on the treatment of SCI.

Spinal cord injury (SCI) is a neurological condition that affects motor and sensory functions below the injury site. The consequences of SCI are devastating for the patients, and although significant efforts have been done in the last years, there is no effective therapy. Baclofen has emerged in the last few years as an interesting drug in the SCI field. Already used in the SCI clinical setting to control spasticity, baclofen has shown important impact on SCI recovery in animal models, such as lampreys and mice.

Herein, we proposed to go deeper into baclofen's mechanism of action and to study its role on the modulation of the immune response after SCI, a major process associated with the severeness of the lesion. Using a SCI compression mice model, we confirmed that baclofen leads to higher locomotor performance, but only at 1 mg·kg-1 and not in higher concentrations, as 5 mg·kg-1. Moreover, we found that baclofen at 1 mg·kg-1 can strongly modulate the immune response after SCI at local, systemic and peripheric levels. This is interesting and intriguingly at the same time, since now, additional studies should be performed to understand if the modulation of the immune response is the responsible for the locomotor outcomes observed on Baclofen treated animals.

Our findings showed, for the first time, that baclofen can modulate the immune response after SCI, becoming a relevant drug in the field of the immunomodulators.

Spinal cord injury (SCI) triggers secondary damage, including pain-induced hypertension, inflammation, and hemorrhage, impairing recovery. This study evaluated the efficacy of general anesthesia with preemptive propofol administration in mitigating secondary damage in SCI rats. SCI was induced in rats using a contusion model. Propofol (100 mg/kg) was administered intraperitoneally either 30 min before (preemptive) or 30 min after intermittent tail shock. Systolic blood pressure (SBP), body weight, food intake, inflammatory markers (interleukin-1 beta [IL-1β], interleukin-6 [IL-6]), hemorrhage markers, and serum levels of SCI biomarkers (glial fibrillary acidic protein [GFAP], myelin basic protein [MBP]) were measured. Functional recovery was assessed over 28 days using the Basso, Beattie, and Bresnahan (BBB) scale, horizontal ladder test, and rotarod test. Preemptive propofol administration effectively mitigated pain-induced hypertension, enhanced body weight and food intake, and reduced inflammatory markers to levels comparable to unstimulated SCI rats. In contrast, propofol administered post-stimulation was less effective. Preemptive administration significantly decreased GFAP levels and preserved MBP levels. Importantly, preemptive intervention reduced levels of hemoglobin and alpha hemoglobin, while post-stimulation intervention showed no significant effect on hemorrhage. Behavioral assessments demonstrated improved locomotor recovery, motor coordination, and balance in preemptively treated rats compared to delayed or no intervention. Preemptive administration of propofol effectively reduces pain-induced hypertension, inflammation, and gliosis while preserving myelin integrity and enhancing functional recovery in SCI rats. This intervention demonstrates significantly greater efficacy compared to delayed administration, underscoring the critical importance of timely treatment in mitigating secondary damage and improving outcomes after SCI.

Spinal cord injury (SCI) presents a formidable challenge in clinical settings, resulting in sensory and motor function loss and imposing significant personal and societal burdens. However, owning to the adverse microenvironment and limited regenerative capacity, achieving complete functional recovery after SCI remains elusive. Additionally, traditional interventions including surgery and medication have a series of limitations that restrict the effectiveness of treatment. Recently, tissue engineering (TE) has emerged as a promising approach for promoting neural regeneration and functional recovery in SCI, which can effectively delivery drugs into injury site and delivery cells and improve the survival and differential. Here, we outline the main pathophysiology events of SCI and the adverse microenvironment post injury, further discuss the materials and common assembly strategies used for scaffolds in SCI treatment, expound on the latest advancements in treatment methods based on materials and scaffolds for drug and cell delivery in detail, and propose future directions for SCI repair with TE and highlight potential clinical applications.

Traumatic spinal cord injury (SCI) causes severe central nervous system damage. M2 macrophages within the lesion are crucial for SCI recovery. Our previous research revealed that M2 macrophages transfected with magnetotactic bacteria-derived Mms6 gene can resist ferroptosis and enhance SCI recovery. To address the limitations of M2 macrophage transplantation, we developed lipid nanoparticles (LNPs) encapsulating Mms6 mRNA targeting macrophages (Mms6 mRNA-PS/LNPs). The targeting efficiency and therapeutic effect of these LNPs in SCI mice were evaluated. Intravenous administration of Mms6 mRNA-PS/LNPs delivered more Mms6 mRNAs to lesion-site macrophages than those in the Mms6 mRNA-LNP group, which resulted in enhancing motor function recovery, reducing lesion area and scar formation, and promoting neuronal survival and nerve fiber repair. These effects were nullified when macrophages were depleted. These findings suggest that macrophage-targeted delivery of Mms6 mRNA is a promising therapeutic strategy for promoting spinal cord repair and motor function recovery in patients with traumatic SCI.

Curcumin, a natural active compound derived from plants, is widely used as a pigment across the globe. Research has demonstrated that curcumin possesses neuroprotective properties in spinal cord injuries (SCIs); however, its specific mechanisms of action remain unclear. This study aimed to elucidate the potential mechanisms underlying curcumin's therapeutic effects in SCI.

We screened the targets of curcumin in the treatment of spinal cord injury using network pharmacology across a variety of public databases. The interaction between the compound and the target was analyzed through bioinformatics analysis, molecular docking, and molecular dynamics simulation. Finally, the prediction results were verified by simulating spinal cord injury through oxygen-glucose deprivation (OGD) injury in PC12 cells.

Initial screening indicated 13 core targets involved in mitigating SCI. Curcumin may regulate the HIF pathway, immune cells, inflammation, oxidative stress, and other processes. Matrix metalloproteinase-9 (MMP9), tumor necrosis factor (TNF), interleukin-1β (IL-1β), signal transducer and activator of transcription 3 (STAT3), and caspase 3 (CASP3) were identified as key targets of curcumin in SCI regulation. Molecular docking results demonstrated that curcumin exhibited favorable affinity with the core targets, with MMP9 showing the highest binding affinity (-8.76 kcal/mol). Further studies confirmed that curcumin stably binds with MMP9, and the binding site was located at residues 220-225. Cell counting kit-8 (CCK8) assay results showed that curcumin exerted a good therapeutic effect. Western blot results showed that curcumin inhibited the expression of MMP9 protein but had no significant effect on the expression of TNF-α.

Curcumin exerts its effects on SCI through multiple targets and pathways. Its specific mechanisms involve the inhibition of inflammation, prevention of apoptosis and ferroptosis, and promotion of neuronal repair. MMP9 may be a key target mediating curcumin's protective effects against SCI. These findings provide scientific evidence for further research and development of drugs.

Spinal Cord Injury (SCI) represents a devastating form of central nervous system trauma, where oxidative stress plays a critical role in the ensuing pathology. Targeting oxidative stress presents a viable therapeutic avenue. Teriparatide, a synthetic analog of parathyroid hormone, is conventionally utilized for osteoporosis and bone defect management. Emerging evidence suggests teriparatide's potential in modulating oxidative stress in ischemic stroke, yet its efficacy in SCI remains underexplored.

We investigated the neuroprotective effects of teriparatide in a rat spinal cord injury (SCI) model. Teriparatide was administered to animals post-injury, and functional recovery was assessed using the open field test and Basso-Beattie-Bresnahan (BBB) locomotor rating scale. Molecular analyses included evaluation of Nrf2 pathway activation and antioxidant protein expression via immunofluorescence, Western blot, and ELISA. Additionally, glutathione peroxidase (GSH-PX) activity and malondialdehyde (MDA) levels were measured using commercial assay kits.

We obtained two significant results: Firstly, teriparatide treatment significantly enhanced motor function recovery post-SCI. Secondly, teriparatide upregulated Nrf2 expression, which subsequently increased the production of the antioxidant proteins HO-1 and SOD2, reduced MDA levels in spinal tissues, and boosted GSH-PX activity.

Our findings demonstrate that teriparatide activates the Nrf2/HO-1 antioxidant pathway, effectively mitigating oxidative damage in SCI. This repositioning of an FDA-approved osteoporosis drug presents a clinically translatable strategy for neuroprotection.

Acute and chronic exposure to high altitude causes multiple negative neurological consequences. Further research has shown the efficacy of targeted drugs after acute hypoxia. However, the effects and mechanisms of physical therapy like exercise, on after exposed-induced myelin repair and functional improvements have remained unclear. Here, we explored the efficacy of treadmill training at different intensities on recovery in a rat model of acute hypobaric hypoxia (HH) injury. A 4-week treadmill training scheme was used at 30%, 50%, and 70% of maximum speed. The evolution of oligodendrocyte morphometry was observed by immunofluorescence, and the expressions of myelin-related proteins were detected by western blotting. Transmission electron microscopy (TEM) is used to study fine myelin structure. In addition, the open field test (OFT), elevated plus maze (EPM) and Morris water maze (MWM) were used for the observation of cognitive function recovery. Our study revealed varying degrees of demyelination changes in the cortex and hippocampus following acute hypoxia exposure. Additionally, high-intensity treadmill training enhances oligodendrocyte (OL) maturation, improves myelin-related proteins, and increases myelin sheath thickness, thus facilitating myelin repair, rescuing cognitive function and mood disorders, and preserving normal nerve conduction. Finally, the upregulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) and key enzymes of cholesterol synthesis (HMGCR/FDPS) induced by high-intensity treadmill training was detected. Our results demonstrate that high-intensity treadmill training as a physical therapy via PGC1α and cholesterol synthesis enhances myelin repair and functional restoration, which should provide new insight for the rehabilitation of remyelination by exercise.

Spinal cord injury (SCI) is a severe condition that often leads to permanent functional impairments. The current treatment options are limited and there is a need for more effective treatments. Human umbilical cord mesenchymal stem cells (hUCMSCs) have shown promise in promoting neuroregeneration and modulating immune response. In addition, miR-124-3p has been identified as a potential biomarker for monitoring the progress of neural repair, making it a focus of the present study, which used a rat model of SCI to evaluate the effects of intrathecal hUCMSC transplantation. The present study included three groups: A sham-operated group, an SCI model group receiving PBS and an SCI group receiving hUCMSCs. Neurological function was assessed using the Basso, Beattie and Bresnahan locomotor rating scale and Rivlin inclined plane test on days 1, 3, 7, 14 and 21 post-injury. Histological analysis included hematoxylin and eosin staining to assess tissue morphology, Nissl staining to evaluate neuron survival and immunofluorescence to detect bromodeoxyuridine (BrdU)+/neuron-specific enolase (NSE)+ cells, which indicate neurogenesis. Detection of brain-derived neurotrophic factor (BDNF) protein expression at various time points in rats with spinal cord injury using western blotting. miR-124-3p expression was quantified using reverse transcription-quantitative (RT-q)PCR to assess its potential as a biomarker for SCI recovery. The hUCMSC group showed significant improvements in motor function compared with the control group, particularly on days 7 and 14 post-injury. Histological analysis revealed reduced scar tissue formation and increased neuron survival in the hUCMSC group. Immunofluorescence analysis showed a higher number of BrdU+/NSE+ cells in the hUCMSC group, indicating enhanced neurogenesis. The expression of the neurorepair-related protein BDNF was markedly higher in the hUCMSCs group compared with the control group. Furthermore, RT-qPCR analysis demonstrated a marked upregulation of miR-124-3p in the hUCMSC group, which was correlated with improved functional recovery. The present study demonstrated that intrathecal transplantation of hUCMSCs notably enhanced recovery following SCI, probably by promoting neurogenesis and modulating miR-124-3p expression. miR-124-3p upregulation in the hUCMSC group highlighted its potential as a biomarker for tracking the progress of SCI recovery. These findings provided a foundation for the future clinical applications of hUCMSCs in SCI treatment and the use of miR-124-3p as a monitoring tool.

Spinal cord injury (SCI) is one of the most complex diseases. After SCI, severe secondary injuries can cause intense inflammatory storms and oxidative stress responses, leading to extensive neuronal apoptosis. Effective regulation of inflammation and oxidative stress after SCI remains an unresolved challenge. In this study, resveratrol-loaded nanoparticles coated with neutrophil membranes (NMR) were prepared using the emulsion-solvent evaporation method and membrane encapsulation technology. Multifunctional biomimetic nanoparticles retain neutrophil membrane-related receptors and possess a strong adsorption capacity for inflammatory factors. As a drug carrier, NMR can sustainably release resveratrol for >72 h. Moreover, co-culture studies in vitro show that the NMR help regulate macrophage polarization to relieve inflammatory response, reduce intracellular reactive oxygen species by approximately 50%, and improve mitochondrial membrane potential to alleviate oxidative stress. After injecting NMR into the injury site, it reduces early apoptosis, inhibit scar formation, and promote neural network recovery to improve motor function. This study demonstrates the anti-inflammatory, antioxidant, and neuroprotective effects of NMR, thus providing a novel therapeutic strategy for SCI.

Recent research has identified ferroptosis, a newly recognized form of programmed cell death, is a crucial factor in spinal cord injury (SCI). Tetrahydroberberine (THB) is a tetrahydroisoquinoline alkaloid derived from the tuber of the poppy family plant, Corydalis, which is recognized for its antioxidant and neuroprotective properties. Despite these attributes, the potential protective effects of THB against SCI are yet to be thoroughly investigated. Therefore, the aim of this study was to elucidate the protective effects and underlying mechanisms of action of THB in SCI. A mouse model of SCI was used for the in vivo experiments. Functional recovery was evaluated using the Basso Mouse Scale (BMS), footprint analysis, and hematoxylin and eosin (HE), Masson's trichrome, and Nissl staining. Lipid peroxidation was quantified using malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD). The expression levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and ferroptosis markers were analyzed using western blot (WB) and immunofluorescence (IF) staining. To further elucidate the mechanism through which THB inhibits ferroptosis, an in vitro ferroptosis model was established in PC12 cells using RSL3, a known ferroptosis activator. THB markedly improved tissue and motor function restoration in mice post-SCI, with the BMS score increasing by approximately 50% compared with that in the control group. Lipid peroxidation assays revealed that THB significantly reduced MDA levels and increased GSH and SOD levels. Both in vivo and in vitro experiments demonstrated that THB significantly activated the Nrf2 pathway and inhibited ferroptosis in mice and in PC12 cells. This protective effect was reversed by the Nrf2 inhibitor, ML385, as evidenced by suppression of the Nrf2 pathway, increased lipid peroxidation, and elevated ferroptosis levels. Our in vivo and in vitro experiments indicate that THB promotes functional recovery after SCI by activating the Nrf2 signaling pathway, which attenuates lipid peroxidation and suppresses ferroptosis, thereby contributing to neuronal survival. Our findings contribute to a more comprehensive understanding of how THB exerts its recovery effects in SCI and demonstrate the potential of THB as a novel therapeutic strategy for the clinical management of SCI.

Spinal cord injury (SCI) can cause irreversible trauma to nervous tissue, leading to permanent damage to the patient's motor and sensory functions. Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) can simulate most of the functions of MSCs and are considered an ideal treatment option for SCI. However, the potential mechanism of MSC-EVs treatment for SCI still needs to be explored. We cultured neurons in vitro to investigate the effect of miR-124 on the p62-Keap1-Nrf2 pathway. Besides, MSC-EVs containing miR-124 were injected into a rat spinal cord injury model to observe their neural repair effect. The accumulation of p62 can be reversed by miR-124, which promotes autophagy and alleviates oxidative stress, thereby exerting neuroprotective effects. Rats who received injection of MSC-EVs overexpressing miR-124 after surgery showed higher BBB scores, lower levels of cell apoptosis, and better spinal cord tissue morphology. Our results indicated that miR-124 can stabilize the p62-Keap1-Nrf2 loop, thereby promoting autophagy and alleviating oxidative stress to exert neuroprotective effects. Our research proposes a novel potential target for treating SCI.

Aside from its immediate traumatic effects, spinal cord injury (SCI) presents multiple secondary complications that can be harmful to those who have been affected by SCI. Among these secondary effects, gut dysbiosis (GD) and the activation of the NOD (nucleotide-binding oligomerization domain) like receptor-family pyrin-domain-containing three (NLRP3) inflammasome are of special interest for their roles in impacting mental health. Studies have found that the state of the gut microbiome is thrown into disarray after SCI, providing a chance for GD to occur. Metabolites such as short-chain fatty acids (SCFAs) and a variety of neurotransmitters produced by the gut microbiome are hampered by GD. This disrupts healthy cognitive processes and opens the door for SCI patients to be impacted by mental health disorders. Additionally, some studies have found an increased presence and activation of the NLRP3 inflammasome and its respective parts in SCI patients. Preclinical and clinical studies have shown that NLRP3 inflammasome plays a key role in the maturation of pro-inflammatory cytokines that can initiate and eventually aggravate mental health disorders after SCI. In addition to the mechanisms of GD and the NLRP3 inflammasome in intensifying mental health disorders after SCI, this review article further focuses on three promising treatments: fecal microbiome transplants, phytochemicals, and melatonin. Studies have found these treatments to be effective in combating the pathogenic mechanisms of GD and NLRP3 inflammasome, as well as alleviating the symptoms these complications may have on mental health. Another area of focus of this review article is exploring how artificial intelligence (AI) can be used to support treatments. AI models have already been developed to track changes in the gut microbiome, simulate drug-gut interactions, and design novel anti-NLRP3 inflammasome peptides. While these are promising, further research into the applications of AI for the treatment of mental health disorders in SCI is needed.

Spinal cord injury (SCI) poses a substantial challenge in contemporary medicine, significantly impacting patients and society. Emerging research highlights a strong association between SCI and chronic pain, yet the molecular mechanisms remain poorly understood. To address this, we conducted bioinformatics and systems biology analyses to identify molecular biomarkers and pathways that link SCI to chronic pain. This study aims to elucidate these mechanisms and identify potential therapeutic targets.

Through analysis of the GSE151371 and GSE177034 databases, we identified differentially expressed genes (DEGs) linked to SCI and chronic pain. This analysis uncovered shared pathways, proteins, transcription factor networks, hub genes, and potential therapeutic drugs. Regression analysis on the hub genes facilitated the development of a prognostic risk model. Additionally, we conducted an in-depth examination of immune infiltration in SCI to elucidate its correlation with chronic pain.

Analyzing 101 DEGs associated with SCI and chronic pain, we constructed a protein interaction network and identified 15 hub genes. Using bioinformatics tools, we further identified 4 potential candidate genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed a strong correlation between SCI and chronic pain, particularly related to inflammation. Additionally, we examined the relationship between SCI and immune cell infiltration, discovering a significant link between SCI and T cell activation. This is notable as activated T cells can cause persistent inflammation and chronic pain. Lastly, we analyzed the hub genes to explore the transcription factor network, potential therapeutic drugs, and ceRNA networks.

The analysis of 15 hub genes as significant biological markers for SCI and chronic pain has led to the identification of several potential drugs for treatment.

Adaptive immune response is at the core of the mechanism of secondary spinal cord injury (SCI). This study aims to explore the molecular mechanism by which classical dendritic cells (cDC1s) influence CD8+ T cell expansion in SCI.

Peripheral blood samples from patients with SCI and spinal cord tissues from SCI mice were collected, and the population of cDC1 subset was analyzed by flow cytometry. In vivo, the fms-like tyrosine kinase 3 (Flt3) inhibitor quizartinib was administered to deplete cDC1s, while intraperitoneal injection of recombinant Flt3L and immunosuppressive drug FTY-720 was used to expand cDC1s and prevent T cell egress from lymph nodes (LNs), respectively. In vitro, the conditioned medium (CM) of isolated LN fibroblastic stromal cells (FSCs) and pre-DCs were co-cultured. Subsequently, FSC CM-induced DCs were stimulated and co-cultured with CD8+ T cells for proliferation assay.

The cDC1 subset was increased in the peripheral blood of SCI patients and in the injured spinal cord of SCI mice. Depletion of cDC1s decreased the proportion of infiltrating CD8+ T cells in the injured spinal cord of SCI mice and reduced the inflammatory response. The Basso Mouse Scale score of SCI mice was increased and the proportion of CD8+ T cells in blood and spinal cord tissue was decreased after FTY-720 injection. Both migratory cDC1s (CD103+) and resident cDC1s (CD8α+) were present in the LNs surrounding the injured spinal cord of SCI mice. Among them, CD103+ cells were derived from the migration of cDC1s in spinal cord tissues, and CD8α+ cDC1s were directionally differentiated from pre-DCs after co-culture with LN-FSCs. Interferon-γ promoted the secretion of Flt3L by LN-FSCs through the activation of JAK/STAT signaling pathway and enhanced the differentiation of pre-DCs into CD8α+ cells.

Migratory cDC1s and resident cDC1s promote the expansion of CD8+ T cells in LNs around the injured spinal cord and mediate the adaptive immune response to aggravate neuroinflammation in SCI.

Current research primarily focuses on the pathological mechanisms of spinal cord injury (SCI), seeking to promote spinal cord repair and restore motorial and sensory functions by elucidating mechanisms of cell death or axonal regeneration. However, SCI is almost irreversible, and patients often struggle to regain mobility or self-care abilities after injuries. Consequently, there has been significant interest in modulating systemic symptoms following SCI to improve patients' quality of life. Neuron axonal disconnection and substantial apoptotic events following SCI result in signal transmission loss, profoundly impacting various organ and systems, including the gastrointestinal tract. Dysbiosis can lead to severe bowel dysfunction in patients, substantially lowering their quality of life and significantly reducing life expectancy of them. Therefore, researches focusing on the restoration of the gut microbiota hold promise for potential therapeutic strategies aimed at rehabilitation after SCI. In this paper, we explore the regulatory roles that dietary fiber, short-chain fatty acids (SCFAs), probiotics, and microbiota transplantation play in patients with SCI, summarize the potential mechanisms of post-SCI dysbiosis, and discuss possible strategies to enhance long-term survival of SCI patients. We aim to provide potential insights for future research aimed at ameliorating dysbiosis in SCI patients.

Spinal cord injury (SCI) triggers a complex inflammatory response that impedes neural repair and functional recovery. The modulation of macrophage phenotypes is thus considered a promising therapeutic strategy to mitigate inflammation and promote regeneration.

We employed microarray and single-cell RNA sequencing (scRNA-seq) to investigate gene expression changes and immune cell dynamics in mice following crush injury at 3 and 7 days post-injury (dpi). High-dimensional gene co-expression network analysis (hdWGCNA) and slingshot trajectory analysis were employed to identify key gene modules and macrophage differentiation pathways. Subsequently, immunofluorescence staining, flow cytometry, and western blotting were performed to validate the identified effects of amantadine on macrophage differentiation and inflammation.

To elucidate the molecular mechanisms underlying the injury response at the transcriptional level, we performed a microarray analysis followed by gene set enrichment analysis (GSEA). The results revealed that pathways related to phagocytosis and macrophage activation are significantly involved post-injury, shedding light on the regulatory role of macrophages in SCI repair. To further investigate macrophage dynamics within the injured spinal cord, we conducted scRNA-Seq, identifying three distinct macrophage subtypes: border-associated macrophages (BAMs), inflammatory macrophages (IMs), and chemotaxis-inducing macrophages (CIMs). Trajectory analysis suggested a differentiation pathway from Il-1b+ IMs to Mrc1+ BAMs, and subsequently to Arg1+ CIMs, indicating a potential maturation process. Given the importance of these pathways in the injury response, we utilized molecular docking to hypothesize that amantadine might modulate this process. Subsequent in vitro and in vivo experiments demonstrated that amantadine reduces Il-1b+ IMs and facilitates the transition to Mrc1+ BAMs and Arg1+ CIMs, likely through modulation of the HIF-1α and NF-κB pathways. This modulation promotes neural regeneration and enhances functional recovery following SCI.

Amantadine modulates macrophage phenotypes following SCI, reduces early inflammatory responses, and enhances neural function recovery. These findings highlight the therapeutic potential of amantadine as a treatment for SCI, and provide a foundation for future translational research into its clinical applications.

Ferroptosis and immune responses are critical pathological events in spinal cord injury (SCI), whereas relative molecular and cellular mechanisms remain unclear.

Micro-array datasets (GSE45006, GSE69334), RNA sequencing (RNA-seq) dataset (GSE151371), spatial transcriptome datasets (GSE214349, GSE184369), and single cell RNA sequencing (scRNA-seq) datasets (GSE162610, GSE226286) were available from the Gene Expression Omnibus (GEO) database. Through weighted gene co-expression network analysis and differential expression analysis in GSE45006, we identified differentially expressed time- and immune-related genes (DETIRGs) associated with chronic SCI and differentially expressed ferroptosis- and immune-related genes (DEFIRGs), which were validated in GSE151371. Protein-protein interaction and microRNA-mRNA-transcription factor regulatory networks were constructed based on Search Tool for the Retrieval of Interacting Genes (STRING) and NetworkAnalyst, respectively, which were validated by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Cell subclusters and unique features of microglia in SCI were identified by single-cell transcriptomic analysis, which were validated in GSE226286. Spatial expression patterns of DETIRGs and DEFIRGs were validated in brain injury (GSE214349) and SCI (GSE184369). Potential mechanisms underlying neuronal regeneration by neurotrophin-3 (NT3)-chitosan were revealed by transcriptomic analyses in GSE69334. Immune- and ferroptosis-related mechanisms of nanolayered double hydroxide loaded with NT3 (LDH-NT3) were investigated in vivo and in vitro.

GBP2, TEC, UNC93B1, PLXNC1, NFATC1, IL10RB, and TLR8 were DETIRGs represented chronic SCI-specific genes and peripheral blood biomarkers. NFKB1 may regulate expression of CYBB and HMOX1 in a unique subcluster of M1 microglia within the middle SCI lesion, establishing links between microglial ferroptosis and neuroinflammation. Reduced inflammatory responses and microglial ferroptosis were potential effects of NT3-chitosan or LDH-NT3 on neuronal regeneration.

A novel subcluster of microglia exhibiting M1 polarization and ferroptosis phenotype was involved in SCI. These microglia may trigger neuroinflammation and induce neuronal degeneration within the middle site of SCI, which might be inhibited by NT3-chitosan or LDH-NT3.

We examine what is known, what is new, and what is emerging in acute neurotrauma relevant to the anesthesiologist.

Timely and goal-directed care is critical for all patients requiring urgent/emergent anesthesia care. Anesthesia care for acute neurological injury should incorporate understanding the evolution of traumatic brain injury and spinal cord injury that translates to preoperative preparation, hemodynamic resuscitation, prevention of second insults, and safe transport between care settings. Anesthesia care should support optimizing patient outcomes.

Best practices involve extrapolating data from the intensive care unit setting since there is a lack of research addressing anesthesia care for acute neurological injury. There are opportunities to generate data to support evidence-based anesthetic care.

An external trauma, illness, or other pathological cause can harm the structure and function of the spinal cord, resulting in a significant neurological disorder known as spinal cord injury (SCI). In addition to impairing movement and sensory functions, spinal cord injury (SCI) triggers complex pathophysiological responses, with the spatial dynamics of immune cells playing a key role. The inflammatory response and subsequent healing processes following SCI are profoundly influenced by the spatial distribution and movement of immune cells. Despite significant advances in both scientific and clinical research, SCI therapy still faces several challenges. These challenges primarily stem from our limited understanding of the spatial dynamics of immune cell distribution and the processes that regulate their interactions within the microenvironment following injury. Therefore, a comprehensive investigation into the spatial dynamics of immune cells following SCI is essential to uncover their mechanisms in neuroinflammation and repair, and to develop novel therapeutic strategies.

Recovery from spinal cord injury (SCI) is often impeded by neuroinflammation, scar formation, and limited axonal regeneration. To tackle these issues, we developed an innovative biomimetic drug delivery system using liquid nitrogen-treated M2 macrophages (LNT M2) which internalized paclitaxel (PTX) nanoparticles beforehand. These were incorporated into a gelatin methacryloyl (GelMA) scaffold, creating a multifunctional, injectable treatment for single-dose administration. The LNT M2 inherited the inflammatory factor/chemokine receptors from the living M2 macrophages and thus possessing significant inflammatory neutralizing effect. In addition, the scaffold provides slow, sustained release of PTX, promoting axonal regeneration and suppressing scar formation in SCI rats. The LNT M2-based dual-functional scaffold significantly enhances motor function, reduces neuroinflammation, and accelerates axonal regeneration by modulating the inflammatory microenvironment and preventing the formation of glial and fibrotic scars. This approach combines the regenerative effects of low-dose PTX with the immunoregulatory properties of LNT M2, leading to remarkable neurological recovery in SCI rats. Moreover, the scaffold's straightforward preparation, ease of standardization, and "ready-to-use" nature make it a promising candidate for acute SCI intervention and future clinical applications.

Non-invasive imaging techniques employing biomarkers with high selectivity for inflammation are essential not only for the early diagnosis and prevention of chronic inflammatory diseases but also for guiding appropriate drug therapy and enabling real-time evaluation of anti-inflammatory drug efficacy. In this study, we conjugated radioactive zirconium to sorbitol, a compound that can selectively target inflammation, and evaluated its inflammation-specific uptake and potential for assessing anti-inflammatory treatment efficacy in a mouse inflammation model. Pharmacokinetic analysis demonstrated that radiolabeled sorbitol achieved maximal uptake in inflamed tissues within 1 h. Positron emission tomography imaging further confirmed its utility in monitoring therapeutic effects during anti-inflammatory drug treatment. Our findings suggest that [89Zr]DTPA-sorbitol is a promising radioprobe for targeting rapid systemic inflammation, particularly in tissues demonstrating minimal non-specific uptake, such as the brain, heart, and lung tissues. Additionally, it holds significant potential for the in vivo evaluation of anti-inflammatory drug efficacy.

This retrospective study evaluates the clinical efficacy of combined electroacupuncture and moxibustion for the treatment of neurogenic bladder in patients with spinal cord injury. Ninety patients with neurogenic bladder after spinal cord injury who were admitted to the hospital between January 2021 and August 2023 were included. The patients were divided into the study and control groups (n = 45 each) using a random number table method. The study group was treated with electroacupuncture combined with moxibustion, while the control group was treated with electroacupuncture alone. The variables evaluated to assess the clinical efficacy of each treatment included number of cases in which bladder function reached a balanced state, initial bladder capacity sensation, maximum detrusor pressure before versus after treatment, maximum urine flow rate, maximum renal pelvic separation width, urine white blood cell count, and subjective quality of life profile score. In the study group, bladder pressure, residual urine volume, frequency of urination, and subjective quality of life profile score increased after versus before treatment (P < .05), whereas the maximal renal pelvis separation width and urinary white blood cell count decreased after versus before treatment (P < .05). Moreover, the study group exhibited significantly greater improvement than the control group (P < .05). The efficacy rates in the study and control groups were 75.6% and 95.6%, respectively; this difference was statistically significant (P < .05). Compared to electroacupuncture alone, electroacupuncture combined with moxibustion reduced the incidence of urinary tract infection, reduced residual urine volume, increased bladder capacity, and achieved balanced bladder function in patients with neurogenic bladder.

Nanoparticles (NPs) offer promising potential as therapeutic agents for inflammation-related diseases, owing to their capabilities in drug delivery and immune modulation. In preclinical studies focusing on spinal cord injury (SCI), polymeric NPs have demonstrated the ability to reprogram innate immune cells. This reprogramming results in redirecting immune cells away from the injury site, downregulating pro-inflammatory signaling, and promoting a regenerative environment post-injury. However, to fully understand the mechanisms driving these effects and maximize therapeutic efficacy, it is crucial to assess NP interactions with innate immune cells. This review examines how the physicochemical properties of polymeric NPs influence their modulation of the immune system. To achieve this, the review delves into the roles played by innate immune cells in SCI and investigates how various NP properties influence cellular interactions and subsequent immune modulation. Key NP properties such as size, surface charge, molecular weight, shape/morphology, surface functionalization, and polymer composition are thoroughly examined. Furthermore, the review establishes connections between these properties and their effects on the immunomodulatory functions of NPs. Ultimately, this review suggests that leveraging NPs and their physicochemical properties could serve as a promising therapeutic strategy for treating SCI and potentially other inflammatory diseases.

Spinal cord injury (SCI) is a neurological disease characterized by high disability and mortality rates. Tomatidine, a natural steroid alkaloid, has been evidenced to have neuroprotective properties. However, the underlying mechanisms of tomatidine in treating SCI remain ambiguous. This study aimed to illustrate the molecular mechanisms of tomatidine in modulating the inflammatory response and promoting functional rehabilitation after SCI.

Sprague-Dawley (SD) rats were used to construct an in vivo SCI model and were intraperitoneally injected with tomatidine (5, 10, or 20 mg/kg) for 7 days, followed by treatment with the nuclear factor-κB (NF-κB) pathway agonist (PMA). In addition, lipopolysaccharide (LPS)-induced PC-12 cells were used to establish an SCI cell model and were stimulated with tomatidine, PMA, or a CXCL10 inhibitor. The pathophysiological changes and neurological function were evaluated using blood-brain barrier (BBB) scoring, water content determination, hematoxylin and eosin (H&E) staining, and TUNEL assay. Levels of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, were measured. Cell proliferation, apoptosis, and the expression of C-X-C motif chemokine ligand 10 (CXCL10) were determined. Moreover, the expression of cleaved-caspase 3, caspase 3, CXCL10, p-p65, and p65 were analyzed.

Our data revealed that tomatidine promoted neuronal damage recovery, reduced histopathological changes, elevated cell proliferation, and inhibited the apoptosis and inflammatory factor levels in spinal cord tissues and LPS-induced PC-12 cells. Moreover, tomatidine decreased the expression of CXCL10 in vitro and in vivo, which was accompanied by the regulation of the NF-κB pathway. However, the NF-κB pathway agonist PMA reversed the protective effect of tomatidine in vitro. PMA also enhanced the CXCL10 expression and stimulated the activation of the NF-κB pathway, as demonstrated by the upregulation of phosphorylated p65. The CXCL10 inhibitor had effects similar to tomatidine on cleaved-caspase 3 expression, CXCL10 expression, and the NF-κB pathway.

Tomatidine can alleviate neuronal damage in SCI by inhibiting apoptosis and inflammation through the NF-κB/CXCL10 pathway. Our findings provide a novel therapeutic target and candidate for the treatment of SCI.