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Traumatic spinal cord injury (TSCI) has significant physical, psychological, and socioeconomic impacts. However, the epidemiological characteristics and treatment patterns of TSCI in South Korea remain unclear. This study aimed to investigate TSCI incidence and treatment behaviors in South Korea from 2008 to 2020. We included data from 30,979 newly diagnosed TSCI patients obtained from the Health Insurance Review and Assessment Service (HIRA). Treatment trends, location of surgery, surgical method, comorbidities, factors affecting hospital stay, and risk factors affecting readmission were analyzed. Patients were divided into the surgery group [n = 7719; (25%)] and the non-surgery group [n = 23,260; (75%)]. Surgical cases involved cervical (64%), thoracic (17%), and lumbar/sacral (19%) lesions. Anterior fusion (38%), posterior fusion (54%), and corpectomy (8%) were the surgical methods. Surgical treatments increased annually. Factors influencing hospital stay included male sex, older age, and higher Charlson comorbidity index (CCI). Female sex and higher CCI scores were associated with readmission. In conclusion, a quarter of all TSCI patients underwent surgery, with an upward trend. Risk factors for longer hospital stays were thoracic spine injury, older age, higher CCI, and male sex. Risk factors for readmission included age range of 40-59 years, lumbar/sacral spine injuries, CCI score of 2, and female sex., (© 2024. The Author(s).)

Background Context: Electrical stimulation is a noninvasive treatment method that has gained popularity in the treatment of spinal cord injury (SCI). Activation of spinal cord-derived neural stem/progenitor cell (SC-NSPC) proliferation and differentiation in the injured spinal cord may elicit considerable neural regenerative effects., Purpose: This study aimed to explore the effect of electrical stimulation on the neurogenesis of SC-NSPCs., Study Design: This study analyzed the effects of electrical stimulation on neurogenesis in rodent SC-NSPCs in vitro and in vivo and evaluated functional recovery and neural circuitry improvements with electrical stimulation using a rodent SCI model., Methods: Rats (20 rats/group) were assigned to sham (Group 1), SCI only (Group 2), SCI + electrode implant without stimulation (Group 3), and SCI + electrode with stimulation (Group 4) groups to count total SC-NSPCs and differentiated neurons and to evaluate morphological changes in differentiated neurons. Furthermore, the Basso, Beattie, and Bresnahan scores were analyzed, and the motor- and somatosensory-evoked potentials in all rats were monitored., Results: Biphasic electrical currents enhanced SC-NSPC proliferation differentiation and caused qualitative morphological changes in differentiated neurons in vitro. Electrical stimulation promoted SC-NSPC proliferation and neuronal differentiation and improved functional outcomes and neural circuitry in SCI models. Increased Wnt3, Wnt7, and β-catenin protein levels were also observed after electrical stimulation., Conclusions: Our study proved the beneficial effects of electrical stimulation on SCI. The Wnt/β-catenin pathway activation may be associated with this relationship between electrical stimulation and neuronal regeneration after SCI., Clinical Significance: The study confirmed the benefits of electrical stimulation on SCI based on cellular, functional, electrophysiological, and histological evidence. Based on these findings, we expect electrical stimulation to make a positive and significant difference in SCI treatment strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

This study was conducted to determine the degree of depression in family caregivers of spinal-cord-injury patients and to identify factors influencing family caregivers' depression. The final study subjects were 30 (family caregivers: 6 males and 24 females). The CES-D of family caregivers; general characteristics of spinal-cord-injury patients and family caregivers; and information on physical health, household income, leisure, social activity, family relationship, and life-in-general status of family caregiver were collected. A frequency analysis, normality test, Mann-Whitney test, Kruskal-Wallis test, Spearman Correlation analysis, hierarchical regression analysis, and spider network through a path model analysis were performed. As for the general characteristics, when the patient was economically active, the caregiver's depression was mean ± SD; 2.04 ± 0.71; otherwise, it was mean ± SD 2.86 ± 0.74, indicating that the caregiver of the non-economic activity patient was more depressed ( p = 0.013). In Model 1 of the multiple regression analysis to understand the effect on the depression of the caregiver, it was confirmed that the depression of the caregiver decreased as the family caregiver had more leisure and social activities (B = -0.718, p = 0.001). In Model 2, it was found that the depression of caregivers increased when the patient did not engage in economic activity (B = 0.438, p = 0.016). In the spider-web form through the path model analysis, as the family's economic level increased, physical health increased by B = 0.755 ( p < 0.001), and the increase in physical health (B = 0.424, p = 0.042) was, in turn, a factor in the increase of engagement in leisure and social activities. Various policies will be needed for the successful return to society of spinal-cord-injury patients by ensuring that their leisure and social activities and establishing measures to support their economical income.

Spinal cord injury (SCI) is associated with limited functional recovery. Despite advances in neuroscience, realistic therapeutic treatments for SCI remain unavailable. In this study, the effects of non-invasive ultrasound (US) treatment on behavior and inflammatory responses were evaluated in a rat model of SCI. Adult female Sprague-Dawley rats were subjected to spinal cord contusion injury. Two different US parameters (SCIU5: 5% and SCIU40: 40% duty cycle) were applied, and their effects on behavioral recovery after SCI were quantified. Tissue and neuronal responses were detected. Immunofluorescence was used to detect inflammatory markers. In the rat model of SCI, motor function was more effectively restored, and the lesion cavity area was smaller in the SCIU5 group. Furthermore, the SCIU5 protocol elicited an anti-inflammatory response at the injury site by reducing degenerative FJC-labeled neurons, macrophage/microglia activation, and infiltration. Thus, the lesion area decreased, and tissue density increased. Meanwhile, the SCIU40 protocol did not improve motor function or induce an anti-inflammatory response at the injury site. The SCIU5 protocol effectively accelerated the rate of improved exercise performance in the rat model while reducing inflammation. Accordingly, appropriate US stimulation may represent a promising treatment modality for SCI with beneficial anti-inflammatory effects., (© 2022. The Author(s).)

After acute traumatic spinal cord injury (SCI), the spinal cord can swell to fill the subarachnoid space and become compressed by the surrounding dura. In a porcine model of SCI, we performed a duraplasty to expand the subarachnoid space around the injured spinal cord and evaluated how this influenced acute intraparenchymal hemodynamic and metabolic responses, in addition to histological and behavioral recovery. Female Yucatan pigs underwent a T10 SCI, with or without duraplasty. Using microsensors implanted into the spinal cord parenchyma, changes in blood flow (ΔSCBF), oxygenation (ΔPO 2 ), and spinal cord pressure (ΔSCP) during and after SCI were monitored, alongside metabolic responses. Behavioral recovery was tested weekly using the Porcine Injury Behavior Scale (PTIBS). Thereafter, spinal cords were harvested for tissue sparing analyses. In both duraplasty and non-animals, the ΔSCP increased ∼5 mm Hg in the first 6 h post-injury. After this, the SCP appeared to be slightly reduced in the duraplasty animals, although the group differences were not statistically significant after controlling for injury severity in terms of impact force. During the first seven days post-SCI, the ΔSCBF or ΔPO 2 values were not different between the duraplasty and control animals. Over 12 weeks, there was no improvement in hindlimb locomotion as assessed by PTIBS scores and no reduction in tissue damage at the injury site in the duraplasty animals. In our porcine model of SCI, duraplasty did not provide any clear evidence of long-term behavioral or tissue sparing benefit after SCI.

There is an increasing need to develop approaches that will not only improve the clinical management of neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI), but also advance therapeutic interventions aimed at recovering bladder function. Although pre-clinical research frequently employs rodent SCI models, large animals such as the pig may play an important translational role in facilitating the development of devices or treatments. Therefore, the objective of this study was to develop a urodynamics protocol to characterize NLUTD in a porcine model of SCI. An iterative process to develop the protocol to perform urodynamics in female Yucatan minipigs began with a group of spinally intact, anesthetized pigs. Subsequently, urodynamic studies were performed in a group of awake, lightly restrained pigs, before and after a contusion-compression SCI at the T2 or T9-T11 spinal cord level. Bladder tissue was obtained for histological analysis at the end of the study. All anesthetized pigs had bladders that were acontractile, which resulted in overflow incontinence once capacity was reached. Uninjured, conscious pigs demonstrated appropriate relaxation and contraction of the external urethral sphincter during the voiding phase. SCI pigs demonstrated neurogenic detrusor overactivity and a significantly elevated post-void residual volume. Relative to the control, SCI bladders were heavier and thicker. The developed urodynamics protocol allows for repetitive evaluation of lower urinary tract function in pigs at different time points post-SCI. This technique manifests the potential for using the pig as an intermediary, large animal model for translational studies in NLUTD.

Resolvins, a new family from the endogenous specialized pro-resolving mediators (SPMs), promote the resolution of the inflammatory response. Resolvin D3 (RvD3), a docosahexaenoic acid (DHA) product, has been known to suppress the inflammatory response. However, the anti-inflammatory and neuroprotective effects of RvD3 are not known in a model of spinal cord injury (SCI). Here, we investigated the anti-inflammatory and neuroprotective effect of RvD3 in a mouse model of SCI. Processes associated with anti-inflammation and angiogenesis were studied in RAW 264.7 cells and the human brain endothelial cell line hCMEC/D3, respectively. Additionally, female C57BL/6 mice were subjected to moderate compression SCI (20-g weight compression for 1 min) followed by intrathecal injection of vehicle or RvD3 (1 μg/20 μL) at 1 h post-SCI. RvD3 decreased the lipopolysaccharide (LPS)-induced production of inflammatory mediators and nitric oxide (NO) in RAW 264.7 cells and promoted an angiogenic effect in the hCMEC/D3 cell line. Treatment with RvD3 improved locomotor recovery and reduced thermal hyperalgesia in SCI mice compared with vehicle treatment at 14 days post-SCI. Remarkably, RvD3-treated mice exhibited reduced expression of inflammatory cytokines (TNF-α, IL6, IL1β) and chemokines (CCL2, CCL3). Also, RvD3-treated mice exhibited increased expression of tight junction proteins such as zonula occludens (ZO)-1 and occludin. Furthermore, immunohistochemistry showed a decreased level of gliosis (GFAP, Iba-1) and neuroinflammation (CD68, TGF-β) and enhanced neuroprotection. These data provide evidence that intrathecal injection of RvD3 represents a promising therapeutic strategy to promote inflammatory resolution, neuroprotection, and neurological functional recovery following SCI.

One of the only currently available treatment options to potentially improve neurological recovery after acute spinal cord injury (SCI) is augmentation of mean arterial blood pressure (MAP) to promote blood flow and oxygen delivery to the injured cord. However, to optimize such hemodynamic management, clinicians require a method to monitor the physiological effects of these MAP alterations within the injured cord. Therefore, we investigated the feasibility and effectiveness of using a novel optical sensor, based on near-infrared spectroscopy (NIRS), to monitor real-time spinal cord oxygenation and hemodynamics during the first 7 days post-injury in a porcine model of acute SCI. Six Yucatan miniature pigs underwent a T10 vertebral level contusion-compression injury. Spinal cord oxygenation and hemodynamics were continuously monitored by a minimally invasive custom-made NIRS sensor, and by invasive intraparenchymal (IP) probes to validate the NIRS measures. Episodes of MAP alteration and hypoxia were performed acutely after injury, and at 2 and 7 days post-injury to simulate the types of hemodynamic changes SCI patients experience after injury. The NIRS sensor demonstrated the ability to provide oxygenation and hemodynamic measurements over the 7-day post-SCI period. NIRS measures showed statistically significant correlations with each of the invasive IP measures and MAP changes during episodes of MAP alteration and hypoxia throughout the first week post-injury ( p  < 0.05). These results indicate that this novel NIRS system can monitor real-time changes in spinal cord oxygenation and hemodynamics over the first 7 days post-injury, and has the ability to detect local tissue changes that are reflective of systemic hemodynamic changes.

Chronic high-thoracic and cervical spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, including impaired left ventricular (LV) contractility. Here, we aim to determine whether such dysfunction manifests immediately post-injury, and if so, whether correcting impaired contractility can improve spinal cord oxygenation (SCO 2 ), blood flow (SCBF) and metabolism. Using a porcine model of T2 SCI, we assess LV end-systolic elastance (contractility) via invasive pressure-volume catheterization, monitor intraparenchymal SCO 2 and SCBF with fiberoptic oxygen sensors and laser-Doppler flowmetry, respectively, and quantify spinal cord metabolites with microdialysis. We demonstrate that high-thoracic SCI acutely impairs cardiac contractility and substantially reduces SCO 2 and SCBF within the first hours post-injury. Utilizing the same model, we next show that augmenting LV contractility with the β-agonist dobutamine increases SCO 2 and SCBF more effectively than vasopressor therapy, whilst also mitigating increased anaerobic metabolism and hemorrhage in the injured cord. Finally, in pigs with T2 SCI survived for 12 weeks post-injury, we confirm that acute hemodynamic management with dobutamine appears to preserve cardiac function and improve hemodynamic outcomes in the chronic setting. Our data support that cardio-centric hemodynamic management represents an advantageous alternative to the current clinical standard of vasopressor therapy for acute traumatic SCI.

Current practice guidelines for acute spinal cord injury (SCI) recommend augmenting mean arterial blood pressure (MAP) for the first 7 days post-injury. After SCI, the cord may be compressed by the bone/ligaments of the spinal column, limiting regional spinal cord blood flow. Following surgical decompression, blood flow may be restored, and can potentially promote a "reperfusion" injury. The effects of MAP augmentation on the injured cord during the compressed and decompressed conditions have not been previously characterized. Here, we used our porcine model of SCI to examine the impact of MAP augmentation on blood flow, oxygenation, hydrostatic pressure, metabolism, and intraparenchymal (IP) hemorrhage within the compressed and then subsequently decompressed spinal cord. Yucatan mini-pigs underwent a T10 contusion injury followed by 2 h of sustained compression. MAP augmentation of ∼20 mm Hg was achieved with norepinephrine (NE). Animals received MAP augmentation either during the period of cord compression (CP), after decompression (DCP), or during both periods (CP-DCP). Probes to monitor spinal cord blood flow (SCBF), oxygenation, pressure, and metabolic responses were inserted into the cord parenchyma adjacent to the injury site to measure these responses. The cord was harvested for histological evaluation. MAP augmentation increased SCBF and oxygenation in all groups. In the CP-DCP group, spinal cord pressure steadily increased and histological analysis showed significantly increased hemorrhage in the spinal cord at and near the injury site. MAP augmentation with vasopressors may improve blood flow and reduce ischemia in the injured cord but may also induce undesirable increases in IP pressure and hemorrhage.

Spinal cord injury (SCI) is a devastating condition of the central nervous system that can lead to permanent motor and sensory deficits. Carbon monoxide-releasing molecule-2 (CORM-2) has been shown to have anti-inflammatory, anti-apoptotic, and angiogenic properties that may be useful for the treatment of SCI. However, it has a short carbon monoxide (CO) release half-life (approximately 1 min). To address this challenge, we developed a CORM-2-incorporated solid lipid nanoparticle (CORM-2-SLN) and evaluated its ameliorating effects for preventing blood-spinal cord barrier (BSCB) disruption and endothelial cell death following SCI. After a moderate compression injury of the spinal cord (compression with a 35-g impounder for 5 min), groups of rats were treated with a CORM-2-solution and CORM-2-SLNs at an equal dose of 10 mg/kg each via an intraperitoneal injection for 8 consecutive days. Behavior analysis was performed and animals were later sacrificed at different time points and evaluated for whether the CORM-2-SLNs prevented BSCB disruption and rescued endothelial cell damage following SCI. The CORM-2-SLN-treated group showed significantly diminished extravasation of Evans Blue dye with enhanced expression of tight junction proteins following SCI. Likewise, significantly diminished endothelial cell markers after SCI were optimally stabilized at 21 days. Additionally, lipopolysaccharide (LPS)-induced loss of tight junction integrity was significantly preserved after CORM-2-SLN treatment in human cerebral microvascular endothelial cell line (hCMEC/D3). Clinically, CORM-2-SLNs were associated with a significantly improved functional recovery, as compared with the CORM-2-solution. CORM-2-SLNs may help potentially to maintain BSCB integrity following SCI.

Traumatic spinal cord injury (SCI) can cause permanent disabilities that seriously reduce quality of life. We evaluated the effects of chronic hyperglycemia before SCI on inflammatory markers and functional recovery after SCI in human patients and a rat model. In the human study, multivariate logistical regression analysis revealed that hemoglobin A1c (HbA1c) values, reflecting average plasma glucose concentration over a 3 month period, at admission were a significant risk factor for poor functional recovery. Moreover, patients with chronic hyperglycemia (HbA1c ≥ 6.5%) had high concentrations of inflammatory biomarkers (interleukin [IL]-6 and IL-8) of cerebrospinal fluid after SCI. Consistent with patient findings, chronic hyperglycemia before SCI in rats was associated with increased inflammatory responses and oxygen-free radicals in the spinal cord and blood, thus resulting in poor functional recovery and histological outcomes. Tight glucose control before SCI decreased the harmful effects of hyperglycemia after SCI in both human and rat studies. Our findings suggest that chronic hyperglycemia before SCI may be a significant prognostic factor with a negative impact on functional and histological outcomes, highlighting the importance of tight glucose control before SCI.

Currently, the role of transient receptor potential vanilloid type 4 (TRPV4), a nonselective cation channel in the pathology of spinal cord injury (SCI), is not recognized. Herein, we report the expression and contribution of TRPV4 in the pathology of scarring and endothelial and secondary damage after SCI. TRPV4 expression increased during the inflammatory phase in female rats after SCI and was expressed primarily by cells at endothelial-microglial junctions. Two-photon microscopy of intracellular-free Ca 2+ levels revealed a biphasic increase at similar time points after SCI. Expression of TRPV4 at the injury epicenter, but not intracellular-free Ca 2+ , progressively increases with the severity of the injury. Activation of TRPV4 with specific agonist altered the organization of endothelial cells, affected tight junctions in the hCMEC/D3 BBB cell line in vitro , and increases the scarring in rat spinal cord as well as induced endothelial damage. By contrast, suppression of TRPV4 with a specific antagonist or in female Trpv4 KO mouse attenuated inflammatory cytokines and chemokines, prevented the degradation of tight junction proteins, and preserve blood-spinal cord barrier integrity, thereby attenuate the scarring after SCI. Likewise, secondary damage was reduced, and behavioral outcomes were improved in Trpv4 KO mice after SCI. These results suggest that increased TRPV4 expression disrupts endothelial cell organization during the early inflammatory phase of SCI, resulting in tissue damage, vascular destabilization, blood-spinal cord barrier breakdown, and scarring. Thus, TRPV4 inhibition/knockdown represents a promising therapeutic strategy to stabilize/protect endothelial cells, attenuate nociception and secondary damage, and reduce scarring after SCI. SIGNIFICANCE STATEMENT TRPV4, a calcium-permeable nonselective cation channel, is widely expressed in both excitable and nonexcitable cells. Spinal cord injury (SCI) majorly caused by trauma/accidents is associated with changes in osmolarity, mechanical injury, and shear stress. After SCI, TRPV4 was increased and were found to be linked with the severity of injury at the epicenter at the time points that were reported to be critical for repair/treatment. Activation of TRPV4 was damaging to endothelial cells that form the blood-spinal cord barrier and thus contributes to scarring (glial and fibrotic). Importantly, inhibition/knockdown of TRPV4 prevented these effects. Thus, the manipulation of TRPV4 signaling might lead to new therapeutic strategies or combinatorial therapies to protect endothelial cells and enhance repair after SCI., (Copyright © 2020 the authors.)

Background Context: Curcumin has anti-inflammatory and antioxidant activities., Objective: This study aimed to investigate the effects of curcumin on the histological changes and functional recovery following spinal cord injury (SCI)., Study Design: One hundred twenty-eight Sprague-Dawley rats were distributed into a sham, SCI only, SCI-hyperglycemia, and SCI-hyperglycemia-curcumin (200 mg/kg/day, i.p.) groups., Methods: SCI was induced using a clip at T9-10 and hyperglycemia was induced by streptozotocin (60-70 mg/kg, i.v.). Plasma malondialdehyde levels and superoxide dismutase activity was measured to determine oxidative stress. The activity of macrophages in the spinal cord after SCI was stained by the anti-CD68 antibody (ED-1). The tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 levels were measured by enzyme-linked immunosorbent assay and Western blot was used to verify the levels of mitogen-activated protein kinases and STAT3. The glial fibrillary acidic protein expression was evaluated by immunofluorescence analysis. Functional recovery was assessed according to the Basso, Beattie, and Bresnahan scale and histologic outcome was evaluated by the lesion volume and spared tissue area., Results: Superoxide dismutase activity increased, the malondialdehyde level decreased, and ED-1 macrophage marker level decreased in the SCI-hyperglycemia-curcumin group than in the SCI-hyperglycemia group at 2 weeks after SCI (p<.01). The SCI-hyperglycemia-curcumin group showed a statistically significant reduction in IL-6, IL-8, and TNF-α levels compared with the SCI-hyperglycemia group after SCI. The phosphorylated-extracellular signal-regulated kinase, phosphorylated-JNK, and phospho-p38 levels were significantly lower in the SCI-hypoglycemia-curcumin group than in the SCI-hypoglycemia group. The SCI-hyperglycemia-curcumin group showed a decrease in glial fibrillary acidic protein expression after SCI compared with the SCI-hyperglycemia group. The SCI-hyperglycemia-curcumin group showed a lower lesion volume, higher spared tissue, and better functional recovery than the SCI-hyperglycemia group., Conclusions: Curcumin may have a potential neuroprotective effect in SCI with hyperglycemia., Clinical Significance: Curcumin decreased the inflammatory response and decreased astrogliosis and improved the functional recovery and histologic outcomes in SCI with hyperglycemia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Despite advances in the treatment of acute spinal cord injury (SCI), measures to mitigate permanent neurological deficits in affected patients are limited. Immediate post-trauma hemodynamic management of patients, to maintain blood supply and improve oxygenation to the injured spinal cord, is currently one aspect of critical care which clinicians can utilize to improve neurological outcomes. However, without a way to monitor the response of spinal cord hemodynamics and oxygenation in real time, optimizing hemodynamic management is challenging and limited in scope. This study aims to investigate the feasibility and validity of using a miniaturized multi-wavelength near-infrared spectroscopy (NIRS) sensor for direct transdural monitoring of spinal cord oxygenation in an animal model of acute SCI. Nine Yorkshire pigs underwent a weight-drop T10 contusion-compression injury and received episodes of ventilatory hypoxia and alterations in mean arterial pressure (MAP). Spinal cord hemodynamics and oxygenation were monitored throughout by a non-invasive transdural NIRS sensor, as well as an invasive intraparenchymal sensor as a comparison. NIRS parameters of tissue oxygenation were highly correlated with intraparenchymal measures of tissue oxygenation. In particular, during periods of hypoxia and MAP alterations, changes of NIRS-derived spinal cord oxygenated hemoglobin and tissue oxygenation percentage corresponded well with the changes in spinal cord oxygen partial pressures measured by the intraparenchymal sensor. Our data confirm that during hypoxic episodes and as changes occur in the MAP, non-invasive NIRS can detect and measure real-time changes in spinal cord oxygenation with a high degree of sensitivity and specificity.

One of the challenges associated with conducting experiments in animal models of traumatic spinal cord injury (SCI) is inducing a consistent injury with minimal variability in the degree of tissue damage and resultant behavioral and biochemical outcomes. We evaluated how the variability in morphometry of the spinal cord and surrounding cerebrospinal fluid (CSF) contributes to the variability in behavioral and histological outcomes in our porcine model of SCI. Using intraoperative ultrasound imaging, spinal cord morphometry was assessed in seven Yucatan minipigs undergoing a weight-drop T10 contusion-compression injury. Bivariate and multi-variate analysis and modeling were used to identify native morphometrical determinants of interanimal variability in histological and behavioral outcomes. The measured biomechanical impact parameters did not correlate with the histological measures or hindlimb locomotor behavior (Porcine Thoracic Injury Behavior Scale). In contrast, clear associations were revealed between CSF layer morphometry and the amount of white matter and tissue sparing. Specifically, the dorsoventral diameter of the dural sac and ventral CSF space were strong predictors of behavioral and histological outcome and together explained ≥95.0% of the variance in these parameters. In addition, a dorsoventral diameter of the spinal cord less than 5.331 mm was a strong contributing factor to poor behavioral recovery over 12 weeks. These results indicate that interanimal variability in cord morphometry provides a potential biological explanation for the observed heterogeneity in histological and behavioral outcomes. Such knowledge is helpful for appropriately balancing experimental groups, and/or varying impact parameters to match cord and CSF layer dimensions for future studies.

After spinal cord injury (SCI), neutrophil elastase (NE) released at injury site disrupts vascular endothelium integrity and stabilization. Angiopoietins (ANGPTs) are vascular growth factors that play an important role in vascular stabilization. We hypothesized that neutrophil elastase is one of the key determinants of vascular endothelium disruption/destabilization and affects angiopoietins expression after spinal cord injury. To test this, tubule formation and angiopoietins expression were assessed in endothelial cells exposed to different concentrations of recombinant neutropil elastase. Then, the expression of angiopoietin-1, angiopoietin-2, and neutrophil elastase was determined at 3 h and at 1, 3, 5, 7, 14, 21, and 28 days in a clinically relevant model of moderate compression (35 g for 5 min at T10) spinal cord injury. A dichotomy between the levels of angiopoietin-1 and angiopoietin-2 was observed; thus, we utilized a specific neutrophil elastase inhibitor (sivelestat sodium; 30 mg/kg, i.p., b.i.d.) after spinal cord injury. The expression levels of neutropil elastase and angiopoietin-2 increased, and that of angiopoietin-1 decreased after spinal cord injury in rats. The sivelestat regimen, optimized via a pharmacokinetics study, had potent effects on vascular stabilization by upregulating angiopoietin-1 via the AKT pathway and preventing tight junction protein degradation. Moreover, sivelestat attenuated the levels of inflammatory cytokines and chemokines after spinal cord injury and hence subsequently alleviated secondary damage observed as a reduction in glial scar formation and the promotion of blood vessel formation and stabilization. As a result, hindlimb locomotor function significantly recovered in the sivelestat-treated animals as determined by the Basso, Beattie, and Bresnahan scale and footprint analyses. Furthermore, sivelestat treatment attenuated neuropathic pain as assessed by responses to von Frey filaments after spinal cord injury. Thus, our result suggests that inhibiting neutropil elastase by administration of sivelestat is a promising therapeutic strategy to inhibit glial scar and promote functional recovery by upregulating angiopoietin-1 after spinal cord injury.

Background Context: Substance P (SP) is a neuropeptide that can influence neural stem/progenitor cell (NSPC) proliferation and neurogenesis in the brain. However, we could not find any experimental study that investigates SP action in the spinal cord., Purpose: The aims of our study were to investigate the potential of the neuropeptide SP in promoting the proliferation of spinal cord-derived NSPCs (SC-NSPCs) after spinal cord injury (SCI) and to clarify the roles of the mitogen-activated protein (MAP) kinase signaling pathway in the process., Study Design: This is a randomized animal study., Methods: The SC-NSPCs were suspended in 100 μL of a neurobasal medium containing SP (binds neurokinin-1 receptor [NK1R]) or L-703,606 (NK1R antagonist) and cultured in a 96-well plate for 5 days. A cell proliferation assay was performed using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. A cord clipping method was used for the SCI model. Substance P and the NK1R antagonist (L-703,606) were infused intrathecally in SCI and sham models. Neural stem/progenitor cell proliferation was evaluated with immunostaining for bromodeoxyuridine (BrdU) and the immature neural marker nestin. An immunoblotting method was used for evaluating the MAP kinase signaling protein that contains extracellular signal-regulated kinases (ERKs and p38) and β-actin as the control group., Results: In vitro, SP (0.01-10 μmol/L) increased the proliferation of cultured SC-NSPCs, with a peak increase of 35±2% at the 0.1 μmol/L concentration. Substance P of 0.1 μmol/L continuously increased SC-NSPC proliferation from 6 hours to 5 days, whereas the proliferation decreased from 18% to 98% with L-703,606 (1-10 μM). Intrathecal infusion of SP (1 μmol/L) for 7 days significantly increased the number of proliferating NPSCs (cells positive for both BrdU and nestin) in the spinal cord (by 120±17%, p<.05) in adult rats, but infusion of L-703,606 (10 μmol/L) significantly decreased the post-SCI induction of NPSC proliferation in the spinal cord (by 87±4%). Also, SP stimulates proliferation of SC-NSPCs via the MAP kinase signaling pathway, especially the phosphorylated ERK and phosphorylated p38 proteins. The phosphorylated ERK and phosphorylated p38 protein levels increased with SP (0.1 μmol/L, p<.05)., Conclusions: These data indicate that SP can promote proliferation of SC-NSPCs in SCI and normal conditions and have important roles in neuronal regeneration after SCI. Also, ERKs and p38 MAP kinases are important signaling proteins in this process., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The purpose of this study was investigating the effects of curcumin on the histological changes and functional recovery following spinal cord injury (SCI) in a rat model. Following either sham operation or SCI, 36 male Sprague-Dawley rats were distributed into three groups: sham group, curcumin-treated group, and vehicle-injected group. Locomotor function was assessed according to the Basso, Beattie, and Bresnahan (BBB) scale in rats who had received daily intraperitoneal injections of 200 mg/kg curcumin or an equivalent volume of vehicle for 7 days following SCI. The injured spinal cord was then examined histologically, including quantification of cavitation. BBB scores were significantly higher in rats receiving curcumin than receiving vehicle (P < 0.05). The cavity volume was significantly reduced in the curcumin group as compared to the control group (P = 0.039). Superoxide dismutase (SOD) activity was significantly elevated in the curcumin group as compared to the vehicle group but was not significantly different from the sham group (P < 0.05, P > 0.05, respectively) at one and two weeks after SCI. Malondialdehyde (MDA) levels were significantly elevated in the vehicle group as compared to the sham group (P < 0.05 at 1 and 2 weeks). MDA activity was significantly reduced in the curcumin group at 2 weeks after SCI when compared to the vehicle group (P = 0.004). The numbers of macrophage were significantly decreased in the curcumin group (P = 0.001). This study demonstrated that curcumin enhances early functional recovery after SCI by diminishing cavitation volume, anti-inflammatory reactions, and antioxidant activity.