Improvement of diabetes-induced spinal cord axon injury with taurine via nerve growth factor-dependent Akt/mTOR pathway.

Diabetic neuropathy (DN) is a common neurological complication caused by diabetes mellitus (DM). Axonal degeneration is generally accepted to be the major pathological change in peripheral DN. Taurine has been evidenced to be neuroprotective in various aspects, but its effect on spinal cord axon injury (SCAI) in DN remains barely reported. This study showed that taurine significantly ameliorated axonal damage of spinal cord (SC), based on morphological and functional analyses, in a rat model of DN induced by streptozotocin (STZ). Taurine was also found to induce neurite outgrowth in cultured cerebral cortex neurons with high glucose exposure. Moreover, taurine up-regulated the expression of nerve growth factor (NGF) and neurite outgrowth relative protein GAP-43 in rat DN model and cultured cortical neurons/VSC4.1 cells. Besides, taurine increased the activating phosphorylation signals of TrkA, Akt, and mTOR. Mechanistically, the neuroprotection by taurine was related to the NGF-pAKT-mTOR axis, because either NGF-neutralizing antibody or Akt or mTOR inhibitors was found to attenuate its beneficial effects. Together, our results demonstrated that taurine promotes spinal cord axon repair in a model of SCAI in STZ-induced diabetic rats, mechanistically associating with the NGF-dependent activation of Akt/mTOR pathway.

Fascin-1 limits myosin activity in microglia to control mechanical characterization of the injured spinal cord.

BACKGROUND: Mechanical softening of the glial scar region regulates axonal regeneration to impede neurological recovery in central nervous system (CNS) injury. Microglia, a crucial cellular component of the glial scar, facilitate neuronal survival and neurological recovery after spinal cord injury (SCI). However, the critical mechanical characterization of injured spinal cord that harmonizes neuroprotective function of microglia remains poorly understood. METHODS: Spinal cord tissue stiffness was assessed using atomic force microscopy (AFM) in a mouse model of crush injury. Pharmacological depletion of microglia using PLX5622 was used to explore the effect of microglia on mechanical characterization. Conditional knockout of Fascin-1 in microglia (Fascin-1 CKO) alone or in combination with inhibition of myosin activity was performed to delve into relevant mechanisms of microglia regulating mechanical signal. Immunofluorescence staining was performed to evaluate the related protein levels, inflammatory cells, and neuron survival after SCI. The Basso mouse scale score was calculated to assess functional recovery. RESULTS: Spinal cord tissue significantly softens after SCI. Microglia depletion or Fascin-1 knockout in microglia limits tissue softening and alters mechanical characterization, which leads to increased tissue pathology and impaired functional recovery. Mechanistically, Fascin-1 inhibits myosin activation to promote microglial migration and control mechanical characterization after SCI. CONCLUSIONS: We reveal that Fascin-1 limits myosin activity to regulate mechanical characterization after SCI, and this mechanical signal should be considered in future approaches for the treatment of CNS diseases.

CSF1R antagonism results in increased supraspinal infiltration in EAE.

BACKGROUND: Colony stimulating factor 1 receptor (CSF1R) signaling is crucial for the maintenance and function of various myeloid subsets. CSF1R antagonism was previously shown to mitigate clinical severity in experimental autoimmune encephalomyelitis (EAE). The associated mechanisms are still not well delineated. METHODS: To assess the effect of CSF1R signaling, we employed the CSF1R antagonist PLX5622 formulated in chow (PLX5622 diet, PD) and its control chow (control diet, CD). We examined the effect of PD in steady state and EAE by analyzing cells isolated from peripheral immune organs and from the CNS via flow cytometry. We determined CNS infiltration sites and assessed the extent of demyelination using immunohistochemistry of cerebella and spinal cords. Transcripts of genes associated with neuroinflammation were also analyzed in these tissues. RESULTS: In addition to microglial depletion, PD treatment reduced dendritic cells and macrophages in peripheral immune organs, both during steady state and during EAE. Furthermore, CSF1R antagonism modulated numbers and relative frequencies of T effector cells both in the periphery and in the CNS during the early stages of the disease. Classical neurological symptoms were milder in PD compared to CD mice. Interestingly, a subset of PD mice developed atypical EAE symptoms. Unlike previous studies, we observed that the CNS of PD mice was infiltrated by increased numbers of peripheral immune cells compared to that of CD mice. Immunohistochemical analysis showed that CNS infiltrates in PD mice were mainly localized in the cerebellum while in CD mice infiltrates were primarily localized in the spinal cords during the onset of neurological deficits. Accordingly, during the same timepoint, cerebella of PD but not of CD mice had extensive demyelinating lesions, while spinal cords of CD but not of PD mice were heavily demyelinated. CONCLUSIONS: Our findings suggest that CSF1R activity modulates the cellular composition of immune cells both in the periphery and within the CNS, and affects lesion localization during the early EAE stages.

Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology.

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the cellular dynamics of MS by modeling temporal and regional rates of disease progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing single-cell spatial expression profiling using in situ sequencing (ISS), we annotated disease neighborhoods and found centrifugal evolution of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course. Single-cell spatial mapping of human archival MS spinal cords confirmed the differential distribution of homeostatic and DA-glia, enabled deconvolution of active and inactive lesions into sub-compartments, and identified new lesion areas. By establishing a spatial resource of mouse and human MS neuropathology at a single-cell resolution, our study unveils the intricate cellular dynamics underlying MS.

Survival Outcome and Prognostic Factors of Primary Spinal Cord Lymphoma.

AIM: To identify the predictive factors associated with the survival of patients with a diagnosis of primary spinal cord lymphoma (PSCL). MATERIAL AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used in this study, which involved 254 patients with PSCL. Data on the patients' age, sex, race, pathology, Ann Arbor stage, adjuvant therapy, and year of diagnosis were collected. Univariate and multivariate Cox regression models were conducted to detect the predictive variables. RESULTS: Of the 254 patients, 67 (26.4%) die from lymphoma at the time of data collection. Cancer-specific survival at 1, 3, and 5 years was 81.0%, 74.6%, and 74.1%, respectively. Diffuse large B-cell lymphoma (DLBL) was the highest prevalent histotype (n=140, 55.1%). The multivariate Cox regression models revealed that chemotherapy (hazard ratio (HR): 0.47; 95% confidence interval (CI), 0.16-0.82; p=0.040) and radiochemotherapy (HR: 0.43; 95% CI, 0.10-0.57; p=0.045) were independent predictors of favorable cancer-specific survival, whereas age - 80 years (HR: 6.51; 95% CI, 1.65-25.64; p=0.003) and DLBL (HR:1.71; 95% CI, 1.02-2.88; p=0.030) were independently associated with poor cancer-specific survival. CONCLUSION: The survival outcome of PSCL is favorable in the current treatment strategy. Chemotherapy and radiochemotherapy were predictors of favorable outcomes, whereas older age and DLBL were associated with poor prognosis.

Scoring Central Nervous System Inflammation, Demyelination, and Axon Injury in Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a common immune-based model of multiple sclerosis (MS). This disease can be induced in rodents by active immunization with protein components of the myelin sheath and Complete Freund's adjuvant (CFA) or by the transfer of myelin-specific T effector cells from rodents primed with myelin protein/CFA into naïve rodents. The severity of EAE is typically scored on a 5-point clinical scale that measures the degree of ascending paralysis, but this scale is not optimal for assessing the extent of recovery from EAE. For example, clinical scores remain high in some EAE models (e.g., myelin oligodendrocyte glycoprotein [MOG] peptide-induced model of EAE) despite the resolution of inflammation. Thus, it is important to complement clinical scoring with histological scoring of EAE, which also provides a means to study the underlying mechanisms of cellular injury in the central nervous system (CNS). Here, a simple protocol is presented to prepare and stain spinal cord and brain sections from mice and to score inflammation, demyelination, and axonal injury in the spinal cord. The method for scoring leukocyte infiltration in the spinal cord can also be applied to score brain inflammation in EAE. A protocol for measuring soluble neurofilament light (sNF-L) in the serum of mice using a Small Molecule Assay (SIMOA) assay is also described, which provides feedback on the extent of overall CNS injury in live mice.

Fisetin orchestrates neuroinflammation resolution and facilitates spinal cord injury recovery through enhanced autophagy in pro-inflammatory glial cells.

BACKGROUND: Neuroinflammation, a critical component of the secondary injury cascade post-spinal cord injury, involves the activation of pro-inflammatory cells and release of inflammatory mediators. Resolution of neuroinflammation is closely linked to cellular autophagy. This study investigates the potential of Fisetin, a natural anti-inflammatory compound, to ameliorate neuroinflammation and confer spinal cord injury protection through the regulation of autophagy in pro-inflammatory cells. METHODS: Utilizing a rat T10 spinal cord injury model with distinct treatment groups (Sham, Fisetin-treated, and Fisetin combined with autophagy inhibitor), alongside in vitro models involving lipopolysaccharide (LPS)-stimulated microglial cell activation and co-culture with neurons, we employed techniques such as transcriptomic sequencing, histological assessments (immunofluorescence staining, etc.), molecular analyses (PCR, WB, ELISA, etc.), and behavioral evaluations to discern differences in neuroinflammation, autophagy, neuronal apoptosis, and neurological function recovery. RESULTS: Fisetin significantly augmented autophagic activity in injured spinal cord tissue, crucially contributing to neurological function recovery in spinal cord-injured rats. Fisetin's autophagy-dependent effects were associated with a reduction in neuronal apoptosis at the injury site. The treatment reduced the population of CD68+ and iNOS+ cells, coupled with decreased pro-inflammatory cytokines IL-6 and TNF-α levels, through autophagy-dependent pathways. Fisetin pre-treatment attenuated LPS-induced pro-inflammatory polarization of microglial cells, with this protective effect partially blocked by autophagy inhibition. Fisetin-induced autophagy in the injured spinal cord and pro-inflammatory microglial cells was associated with significant activation of AMPK and inhibition of mTOR. CONCLUSION: Fisetin orchestrates enhanced autophagy in pro-inflammatory microglial cells through the AMPK-mTOR signaling pathway, thereby mitigating neuroinflammation and reducing the apoptotic effects of neuroinflammation on neurons. This mechanistic insight significantly contributes to the protection and recovery of neurological function following spinal cord injury, underscoring the vital nature of Fisetin as a potential therapeutic agent.

Correlation between morphological parameters and dosimetric parameters of the heart and spinal cord in the intermediate- and advanced-stage esophageal cancer.

BACKGROUND: Radiation therapy plays a pivotal role as the primary adjuvant treatment for esophageal cancer (EPC), emphasizing the critical importance of carefully balancing radiation doses to the target area and organs at risk in the radiotherapeutic management of esophageal cancer. AIMS: This study aimed to explore the correlation between morphological parameters and dosimetric parameters of the heart and spinal cord in intermediate- and advanced-stage esophagus cancer to provide a reference for clinical treatment. METHODS AND RESULTS: A total of 105 patients with intermediate- and advanced-stage EPC, who received treatment in our hospital from 2019 to 2021, were included. The morphological parameters were calculated by imaging. Intensity-modulated radiation therapy plan was executed at Raystation4.7. The PTV-G stood for the externally expanded planning target volume (PTV) of the gross tumor volume (GTV) and PTV-C for the externally expanded volume of the clinical target volume (CTV). The prescription dose of PTV-G and PTV-C was set as 60Gy/30F and 54Gy/30F, respectively. The linear regression model was used to analyze the correlation between morphologic parameters of EPC and dosimetric parameters of the heart and spinal cord. In 105 cases, the total lung length was correlated with the spinal cord maximum dose (D2 ). The heart mean doses (Dmean ) and heart V40 (the relative volume that receives 40 Gy or more) was correlated with PTV-G volume, PTV-G length; In middle- and upper-segment EPC cases, only the total lung volume was correlated with the spinal cord Dmean , spinal cord D2 , heart Dmean , and heart V40 ; In middle-stage EPC cases, the heart Dmean was correlated with the PTV-G volume, PTV-G length. The total lung length was correlated with the spinal cord D2 ; In middle- and lower-segment EPC, only the PTV-G volume and PTV-G length were correlated with the heart Dmean . All the aforementioned values were statistically significant. CONCLUSIONS: Combined with the unsegmented tumor and different locations, the organ at risk dose was comprehensively considered.

CD4+CD25+ regulatory T cells ex vivo generated from autologous naïve CD4+ T cells suppress EAE progression.

CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining immune homeostasis in multiple sclerosis (MS). Hence, we aimed to explore the therapeutic efficacy and safety of adoptive cell therapy (ACT) utilizing induced antigen-specific Tregs in an animal model of MS, that is, in an experimental autoimmune encephalomyelitis (EAE) model. B cells from EAE model that were activated with soluble CD40L were used as antigen-presenting cells (APCs) to induce the differentiation of antigen-specific Tregs from naïve CD4 precursors, and then, a stepwise isolation of CD4+CD25highCD127low Tregs was performed using a flow sorter. All EAE mice were divided into Treg-treated group (2 × 104 cells in 0.2 mL per mouse, n = 14) and sham-treated group (0.2 mL normal saline (NS), n = 20), which were observed daily for clinical assessment, and for abnormal appearance for 6 weeks. Afterward, histological analysis, immunofluorescence and real-time PCR were performed. Compared to sham-treated mice, Treg-treated mice exhibited a significant decrease in disease severity scores and reduced inflammatory infiltration and demyelination in the spinal cord. Additionally, Tregs-treated mice demonstrated higher CCN3 protein and mRNA levels than sham-treated mice. The results of this preclinical study further support the therapeutic potential of this ACT approach in the treatment of MS.

The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study.

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is 'burnt out' and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.

Creating a Reproducible Model of Spinal Cord Injury in Rats: A Contusion Approach.

Spinal cord injury (SCI) is a devastating clinical condition that affects millions of people worldwide. SCI primarily affects males in younger age groups. It is characterized by a complex of neurological dysfunctions that can lead to permanent disability. We describe an adapted technique for SCI, i.e., a contusion model of SCI, in this chapter. This model is widely used to study the pathology of SCI and test potential therapies. The experimental contusion is performed by using a compression device, which allows the creation of a reproducible injury animal model through the definition of specific injury parameters. A detailed methodology has been developed and described here that utilizes a stereotactic frame and impactor to produce reproducible injuries.

Evaluation of the structural integrity of different spinal cord tracts with magnetization transfer ratio in degenerative cervical myelopathy.

PURPOSE: Degenerative cervical myelopathy (DCM) is a common cause of spinal cord dysfunction. In this study, we explored the potential of magnetization transfer ratio (MTR) for evaluating the structural integrity of spinal cord tracts in patients with clinically significant DCM. METHODS: Fifty-three patients with DCM and 41 patients with cervical radiculopathy were evaluated using high-resolution cervical spinal cord magnetic resonance imaging (MRI), which included the magnetization transfer technique. MRI data were analyzed with the Spinal Cord Toolbox (v5.5); MTR values in each spinal tract were calculated and compared between groups after correction for patient age and sex. Correlations between MTR values and patients' clinical disability rate were also evaluated. RESULTS: A statistically significant reduction in the average MTR of the spinal cord white matter, as well as the MTR of the ventral columns and lateral funiculi, was revealed in the DCM group (adjusted p < 0.01 for all comparisons). Furthermore, reductions in MTR values in the fasciculus cuneatus, spinocerebellar, rubrospinal, and reticulospinal tracts were found in patients with DCM (adjusted p < 0.01 for all comparisons). Positive correlations between the JOA score and the MTR within the ventral columns of the spinal cord (R = 0.38, adjusted p < 0.05) and the ventral spinocerebellar tract (R = 0.41, adjusted p < 0.05) were revealed. CONCLUSION: The findings of our study indicate that demyelination in patients with DCM primarily affects the spinal tracts of the extrapyramidal system, and the extent of these changes is related to the severity of the condition.

Atypical and delayed spinal cord MRI features of COVID-19-associated myelopathies: a report of four cases and literature review.

We reported four patients with coronavirus disease 2019 (COVID-19)-associated myelopathies, highlighting the delayed and atypical spinal cord magnetic resonance imaging (MRI) features and the literature review. All four patients were males, aged 37 to 72 years old. The latencies from COVID-19 to the onset of myelitis were 5, 15, 30, and 80 days. The initial symptoms were numbness and weakness of lower limbs in three cases, and back pain with weakness of lower limbs in one case. The peak symptoms included paraplegia, sphincter dysfunction, sensory disturbance level, and spastic gait. The EDSS scores were 7.5, 9.0, 9.0, and 7.5, respectively. Magnetic resonance imaging (MRI) showed delayed atypical spinal cord lesions at onset, i.e., two cases without lesions, one with linear spinal meningeal enhancement, and one with punctate lesions on T2-weighted imaging (T2WI). During the follow-up period, punctate, linear, and cloudy lesions in the lateral and posterior funiculus were seen on T2WI in the peak stage. The prominent features of spinal cord lesions were linear spinal meningeal enhancement, the mismatch of deteriorated clinical symptoms, and inapparent MRI findings. All four patients were left with an obvious disability, with two patients completely bedridden and two who could stand with support. This report highlights the recognition of COVID-19-associated myelopathy even months after initial infection, especially in patients with delayed and atypical spinal cord findings on MRI.

Association of spinal cord abnormalities with vertebral anomalies: an embryological perspective.

PURPOSE: To analyze the relationship between spinal cord and vertebral abnormalities from the point of view of embryology. METHODS: We analyzed the clinical and radiological data of 260 children with different types of spinal cord malformations in combination with vertebral abnormalities. RESULTS: Among 260 individuals, approximately 109 presented with open neural tube defects (ONTDs), 83 with split cord malformations (SCMs), and 83 with different types of spinal lipomas. Pathological spina bifida emerged as the most frequent vertebral anomaly, affecting 232 patients, with a higher prevalence in ONTD. Vertebral segmentation disorders, including unsegmented bars, butterfly vertebrae, and hemivertebrae, were present in 124 cases, with a higher prevalence in SCM. The third most common spinal anomaly group consisted of various forms of sacral agenesis (58 cases), notably associated with blunt conus medullaris, spinal lipomas, and sacral myelomeningocele. Segmental aplasia of the spinal cord had a typical association with segmental spinal absence (N = 17). CONCLUSION: The association between SCM and neuroenteric cyst/canal and vertebral segmentation disorders is strong. High ONTDs often coincide with pathological spina bifida posterior. Type 1 spinal lipomas and focal spinal nondisjunction also correlate with pathologic spina bifida. Segmental spinal absence or dysgenesis involves localized spinal and spinal cord aplasia, sometimes with secondary filar lipoma.

Neuron-astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain.

Long-lasting pain stimuli can trigger maladaptive changes in the spinal cord, reminiscent of plasticity associated with memory formation. Metabolic coupling between astrocytes and neurons has been implicated in neuronal plasticity and memory formation in the central nervous system, but neither its involvement in pathological pain nor in spinal plasticity has been tested. Here we report a form of neuroglia signalling involving spinal astrocytic glycogen dynamics triggered by persistent noxious stimulation via upregulation of the Protein Targeting to Glycogen (PTG) in spinal astrocytes. PTG drove glycogen build-up in astrocytes, and blunting glycogen accumulation and turnover by Ptg gene deletion reduced pain-related behaviours and promoted faster recovery by shortening pain maintenance in mice. Furthermore, mechanistic analyses revealed that glycogen dynamics is a critically required process for maintenance of pain by facilitating neuronal plasticity in spinal lamina 1 neurons. In summary, our study describes a previously unappreciated mechanism of astrocyte-neuron metabolic communication through glycogen breakdown in the spinal cord that fuels spinal neuron hyperexcitability.

Evaluation of Conditions for the Development of Cryogenic Spinal Cord Injury Using a Canine Model: An Experimental Study on the Safety of Cryoablation for Metastatic Spinal Tumors.

BACKGROUND AND PURPOSE: Although the application of cryoablation to metastatic spinal tumors has been attempted, spinal cryoablation has the unique complication of cryogenic spinal cord injury. This study aimed to elucidate the conditions for the development of cryogenic spinal cord injury. MATERIALS AND METHODS: Fifteen canines were used in this study. A metal probe was inserted into the 13th thoracic vertebral body. Cryoablation was performed for 10 minutes by freezing the probe in liquid nitrogen. The control canine underwent probe insertion only. Spinal cord monitoring, epidural temperature measurement, motor function assessment, and pathologic examination of the spinal cord were performed. RESULTS: During the 10 minutes of cryoablation, the epidural temperature decreased and reached the lowest epidural temperature (LET) at the end of cryoablation. The LETs (degrees celsius [°C]) of each canine were -37, -30, -27, -8, -3, -2, 0, 1, 4, 8, 16, 18, 20, and 25, respectively. As the epidural temperature decreased, waveform amplitudes also decreased. At the end of cryoablation (10 minutes after the start of cryoablation), abnormal waves were observed in 92.9% (13/14) of canines. With epidural rewarming, the amplitude of the waveforms tended to recover. After epidural rewarming (2 hours after the start of cryoablation), abnormal waves were observed in 28.6% (4/14) of canines. The LETs (°C) of the canines with abnormal waves after epidural rewarming were -37, -30, -27, and -8. None of the canines with normal waves after epidural rewarming had any motor impairment. In contrast, all canines with remaining abnormal waves after epidural rewarming had motor impairment. In the pathologic assessment, cryogenic changes were found in canines with LETs (°C) of -37 -30, -27, -8, 0, and 1. CONCLUSIONS: This study showed that 10-minute spinal cryoablation with LETs (°C) of -37, -30, -27, -8, 0, and 1 caused cryogenic spinal cord injury. There was no evidence of cryogenic spinal cord injury in canines with LET of ≥4°C. The epidural temperature threshold for cryogenic spinal cord injury is between 1 and 4°C, suggesting that the epidural temperature should be maintained above at least 4°C to prevent cryogenic spinal cord injury.

Functional plasticity of glutamatergic neurons of medullary reticular nuclei after spinal cord injury in mice.

Spinal cord injury disrupts the descending command from the brain and causes a range of motor deficits. Here, we use optogenetic tools to investigate the functional plasticity of the glutamatergic reticulospinal drive of the medullary reticular formation after a lateral thoracic hemisection in female mice. Sites evoking stronger excitatory descending drive in intact conditions are the most impaired after injury, whereas those associated with a weaker drive are potentiated. After lesion, pro- and anti-locomotor activities (that is, initiation/acceleration versus stop/deceleration) are overall preserved. Activating the descending reticulospinal drive improves stepping ability on a flat surface of chronically impaired injured mice, and its priming enhances recovery of skilled locomotion on a horizontal ladder. This study highlights the resilience and capacity for reorganization of the glutamatergic reticulospinal command after injury, along with its suitability as a therapeutical target to promote functional recovery.

Bioadhesive Hyaluronic Acid-Based Hydrogels for Spinal Cord Injury.

Spinal cord injuries (SCI) have devastating physical, psychological, and psychosocial consequences for patients. One challenge of nerve tissue repair is the lack of a natural extracellular matrix (ECM) that guides the regenerating axons. Hyaluronic acid (HA) is a major ECM component and plays a fundamental role in facilitating lesion healing. Herein, we developed HA-based adhesive hydrogels by modification of HA with dopamine, a mussel-inspired compound with excellent adhesive properties in an aqueous environment. The hydrogels were loaded with the anti-inflammatory drug ibuprofen and the response of neuronal cells (SH-SY5Y) was evaluated in terms of viability, morphology, and adhesion. The obtained results suggested that the developed materials can bridge lesion gaps, guide axonal growth, and simultaneously act as a vehicle for the delivery of bioactive compounds.

Grafted human-induced pluripotent stem cells-derived oligodendrocyte progenitor cells combined with human umbilical vein endothelial cells contribute to functional recovery following spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a devastating disease that causes extensive damage to oligodendrocytes and neurons leading to demyelination and axonal degeneration. In this study, we co-transplanted cell grafts containing oligodendrocyte progenitor cells (OPCs) derived from human-induced pluripotent stem cells (iPSCs) combined with human umbilical vein endothelial cells (HUVECs), which were reported to promote OPCs survival and migration, into rat contusion models to promote functional recovery after SCI. METHODS: OPCs were derived from iPSCs and identified by immunofluorescence at different time points. Functional assays in vitro were performed to evaluate the effect of HUVECs on the proliferation, migration, and survival of OPCs by co-culture and migration assay, as well as on the neuronal axonal growth. A combination of OPCs and HUVECs was transplanted into the rat contusive model. Upon 8 weeks, immunofluorescence staining was performed to test the safety of transplanted cells and to observe the neuronal repairment, myelination, and neural circuit reconstruction at the injured area; also, the functional recovery was assessed by Basso, Beattie, and Bresnahan open-field scale, Ladder climb, SEP, and MEP. Furthermore, the effect of HUVECs on grafts was also determined in vivo. RESULTS: Data showed that HUVECs promote the proliferation, migration, and survival of OPCs both in vitro and in vivo. Furthermore, 8 weeks upon engraftment, the rats with OPCs and HUVECs co-transplantation noticeably facilitated remyelination, enhanced functional connection between the grafts and the host and promoted functional recovery. In addition, compared with the OPCs-alone transplantation, the co-transplantation generated more sensory neurons at the lesion border and significantly improved the sensory functional recovery. CONCLUSIONS: Our study demonstrates that transplantation of OPCs combined with HUVECs significantly enhances both motor and sensory functional recovery after SCI. No significance was observed between OPCs combined with HUVECs group and OPCs-alone group in motor function recovery, while the sensory function recovery was significantly promoted in OPCs combined with HUVECs groups compared with the other two groups. These findings provide novel insights into the field of SCI research.

Sodium aescinate ameliorates chronic neuropathic pain in male mice via suppressing JNK/p38-mediated microglia activation.

OBJECTIVE: A study confirmed that sodium aescinate (SA) can effectively relieve bone cancer pain, but its role in neuropathic pain (NP) remains confused. METHODS: Eighty male mice were randomly divided into four groups: sham+vehicle, sham+SA (40 µg/L, intrathecal injection), chronic contraction injury (CCI)+vehicle, CCI+SA. Behavioral assessments were used to evaluate the locomotor activity and paw withdrawal threshold (PWT) of mice. At the end of the study, spinal cord tissues were collected for histopathological analysis. The JNK/p38 signaling activation, Iba-1 expression, pro-inflammatory cytokines levels, and microglia subtype were assessed by western blotting, immunohistochemical staining, enzyme-linked immunosorbent assay, and flow cytometry with CD86/CD206, respectively. RESULTS: Early treatment with SA delayed the development of mechanical allodynia in CCI mice. Repeated SA treatment could prominently increase the reduction of PWT induced by CCI, and improve the locomotor activity of CCI mice. Mechanically, CCI surgery induced significant up-regulation of p-JNK and p-p38 protein levels, increased number and M1/M2 ratio of microglia, as well as pro-inflammatory factors in the spinal cords of mice, which could be blocked after SA administration. CONCLUSIONS: SA might suppress the activation of microglia and neuroinflammation by selectively inhibiting the JNK/p38 signaling pathway, thereby alleviating CCI-induced NP in male mice.