Search

Increased mechanical stress after spinal cord injury (SCI) expands the scope of nerve tissue damage and exacerbates nerve function defects. Surgical decompression after SCI is a conventional therapeutic strategy and has been proven to have neuroprotective effects. However, the mechanisms of the interaction between mechanical stress and neurons are currently unknown. In this study, we monitored intramedullary pressure (IMP) and investigated the therapeutic benefit of decompression (including durotomy and piotomy) after injury and its underlying mechanisms in SCI. We found that decreased IMP promotes the generation and degradation of LC3 II, promotes the degradation of p62 and enhances autophagic flux to alleviate apoptosis. The lysosomal dysfunction was reduced after decompression. Piotomy was better than durotomy for the histological repair of spinal cord tissue after SCI. However, the autophagy‐lysosomal pathway inhibitor chloroquine (CQ) partially reversed the apoptosis inhibition caused by piotomy after SCI, and the structural damage was also aggravated after CQ administration. An antibody microarray analysis showed that decompression may reverse the up‐regulated abundance of p‐PI3K, p‐AKT and p‐mTOR caused by SCI. Our findings may contribute to a better understanding of the mechanism of decompression and the effects of mechanical stress on autophagy after SCI.

Spinal cord injury (SCI) disturbs the autonomic nervous system and induces dysfunction in multiple organs/tissues, such as the gastrointestinal (GI) system. The neuroprotective effects of melatonin in SCI models have been reported; however, it is unclear whether the beneficial effects of melatonin are associated with alleviation of gut dysbiosis. In this study, we showed that daily intraperitoneal injection with melatonin following spinal cord contusion at thoracic level 10 in mice improved intestinal barrier integrity and GI motility, reduced expression levels of certain proinflammatory cytokines, improved animal weight gain and metabolic profiling, and promoted locomotor recovery. Analysis of gut microbiome revealed that melatonin treatment decreased the Shannon index and reshaped the composition of intestinal microbiota. Melatonin-treated SCI animals showed decreased relative abundance of Clostridiales and increased relative abundance of Lactobacillales and Lactobacillus, which correlated with alteration of cytokine (monocyte chemotactic protein 1) expression and GI barrier permeability, as well as with locomotor recovery. Experimental induction of gut dysbiosis in mice before SCI (i.e., by oral delivery of broad-spectrum antibiotics) exacerbates neurological impairment after SCI, and melatonin treatment improves locomotor performance and intestinal integrity in antibiotic-treated SCI mice. The results suggest that melatonin treatment restores SCI-induced alteration in gut microbiota composition, which may underlie the ameliorated GI function and behavioral manifestations.

It has been previously reported that the blockade of interleukin-7 receptor (IL-7R) promotes functional recovery following spinal cord injury (SCI), however, the direct function and molecular mechanism of IL-7 involved in this pathogenic process are unclear. Here, we report that, contrary to IL-7R blockade, the intraspinal administration of IL-7 limits functional recovery following SCI. In addition, IL-7 treatment promotes neuronal apoptosis in spinal cord lesions, which may be attributed to exacerbated focal inflammatory response, as shown by increased accumulation of activated microglia/macrophage and production of proinflammatory mediators. Moreover, IL-7 treatment activates JAK/STAT5 pathway following SCI. At last, more importantly, the pharmacological inhibition of STAT5 abrogates the effects of IL-7 treatment on functional recovery, neuronal apoptosis and focal inflammatory response, suggesting that the effects of IL-7 treatment following SCI are dependent on activating the JAK/STAT5 pathway. Overall, this study reveals the JAK/STAT5 pathway-dependent detrimental role of IL-7 following SCI, and also implies that targeting the IL-7/JAK/STAT5 axis may represent a potential therapeutic approach for SCI treatment.

Additional file 7: Table S2. Analysis of composition of microbiomes (ANCOM) between groups with values corrected for multiple comparisons using False Discovery Rate (FDR).

Additional file 6: Table S1. Fecal SCFAs contents in different groups.

Surgical decompression after spinal cord injury (SCI) is a conventional treatment. Although it has been proven to have clinical effects, there are certain limitations, such as the surgical conditions that must be met and the invasive nature of the treatment. Therefore, there is an urgent need to develop a simple and maneuverable therapy for the emergency treatment of patients with SCI before surgery. Rapamycin (RAPA) has been reported to have potential as a therapeutic agent for SCI. In this study, we observed the therapeutic effects of rapamycin and surgical decompression, in combination or separately, on the histopathology in rabbits with SCI. After combination therapy, intramedullary pressure (IMP) decreased significantly, autophagic flux increased, and apoptosis and demyelination were significantly reduced. Compared with RAPA/surgical decompression alone, the combination therapy had a significantly better effect. In addition, we evaluated the effects of mechanical pressure on autophagy after SCI by assessing changes in autophagic initiation, degradation, and flux. Increased IMP after SCI inhibited autophagic degradation and impaired autophagic flux. Decompression improved autophagic flux after SCI. Our findings provide novel evidence of a promising strategy for the treatment of SCI in the future. The combination therapy may effectively improve emergency treatment after SCI and promote the therapeutic effect of decompression. This study also contributes to a better understanding of the effects of mechanical pressure on autophagy after neurotrauma.

Surgical decompression after spinal cord injury (SCI) is a conventional treatment. Although it has been proven to have clinical effects, there are certain limitations, such as the surgical conditions that must be met and the invasive nature of the treatment. Therefore, there is an urgent need to develop a simple and maneuverable therapy for the emergency treatment of patients with SCI before surgery. Rapamycin (RAPA) has been reported to have potential as a therapeutic agent for SCI. In this study, we observed the therapeutic effects of rapamycin and surgical decompression, in combination or separately, on the histopathology in rabbits with SCI. After combination therapy, intramedullary pressure (IMP) decreased significantly, autophagic flux increased, and apoptosis and demyelination were significantly reduced. Compared with RAPA/surgical decompression alone, the combination therapy had a significantly better effect. In addition, we evaluated the effects of mechanical pressure on autophagy after SCI by assessing changes in autophagic initiation, degradation, and flux. Increased IMP after SCI inhibited autophagic degradation and impaired autophagic flux. Decompression improved autophagic flux after SCI. Our findings provide novel evidence of a promising strategy for the treatment of SCI in the future. The combination therapy may effectively improve emergency treatment after SCI and promote the therapeutic effect of decompression. This study also contributes to a better understanding of the effects of mechanical pressure on autophagy after neurotrauma.

Background Spinal cord injury (SCI) patients display disruption of gut microbiome, and gut dysbiosis exacerbate neurological impairment in SCI models. Cumulative data support an important role of gut microbiome in SCI. Here, we investigated the hypothesis that fecal microbiota transplantation (FMT) from healthy uninjured mice into SCI mice may exert a neuroprotective effect. Results FMT facilitated functional recovery, promoted neuronal axonal regeneration, improved animal weight gain and metabolic profiling, and enhanced intestinal barrier integrity and GI motility in SCI mice. High-throughput sequencing revealed that levels of phylum Firmicutes, family Christensenellaceae, and genus Butyricimonas were reduced in fecal samples of SCI mice, and FMT remarkably reshaped gut microbiome. Also, FMT-treated SCI mice showed increased amount of fecal short-chain fatty acids (SCFAs), which correlated with alteration of intestinal permeability and locomotor recovery. Furthermore, FMT downregulated IL-1β/NF-κB signaling in spinal cord and NF-κB signaling in gut following SCI. Conclusion Our study demonstrates that reprogramming of gut microbiota by FMT improves locomotor and GI functions in SCI mice, possibly through the anti-inflammatory functions of SCFAs.

Patients with spinal cord injury (SCI) have an increased risk for developing type 2 diabetes. It is unknown whether the pancreatic-islet microvascular vasomotion is involved. We used female C57BL/6 mice and a 100-kilodyne T10 Infinite Horizons contusion SCI (or T10 laminectomy) to detect blood glucose and pancreatic-islet microvascular vasomotion. Blood glucose obtained from tail vein was detected using one Touch UltraEasy glucometer. Glucose tolerance test was performed by d-glucose administration intraperitoneally. Functional status of pancreatic-islet microvascular vasomotion was determined by laser Doppler monitoring. Expressions of insulin and glucagon were determined by immunohistochemistry. Expression of VEGF-A was determined by immunohistochemistry and Western blotting. Our result demonstrated that blood glucose was significantly increased at 4 h postinjury compared to that in sham group, with continuous higher blood glucose until 4 days postinjury (p 0.05). SCI mice at day 7 and day 14 had significantly impaired glucose tolerance following glucose administration (p 0.01). Average blood perfusion, amplitude, frequency, and relative velocity of vasomotion were significantly lower at 6 h postinjury than those in the sham group (p 0.05), which were gradually upregulated over time. The expression of insulin was decreased, while the expression of glucagon was increased at 6 h postinjury. Similarly, the expression of VEGF-A was significantly decreased at 6 h postinjury, compared to that in sham group (p 0.05), with slight increases by 14 days postinjury. Our study suggests that the functional status of pancreatic-islet microvascular vasomotion is impaired after injury, which may have implications for developing effective therapeutic interventions for SCI.

Neurogenic bowel dysfunction (NBD) and gut dysbiosis frequently occur in patients with traumatic cervical spinal cord injury (TCSCI). We evaluated neurogenic bowel management and changes in the gut microbiota in patients with TCSCI as well as associations between these changes and serum biomarkers. Fresh fecal and clinical data were collected from 20 male patients with TCSCI and 23 healthy males. Microbial diversity and composition were analyzed by sequencing the V3-V4 region of the 16S rRNA gene. Moderate NBD was observed in patients with TCSCI. The diversity of the gut microbiota was lower in patients with TCSCI than in healthy adults. Furthermore, patients with TCSCI showed altered levels of serum biomarkers related to lipid metabolism, indicating unfavorable lipid profiles. Interestingly, Firmicutes had a positive effect and Verrucomicrobia had a negative effect on lipid metabolism (P < 0.05). At the genus level, Bacteroides and Blautia were significantly more abundant in patients than in healthy subjects and could be associated with lipid metabolism (P < 0.05). Faecalibacterium, Megamonas, and Prevotella, which were correlated with lipid metabolism markers, may be suitable targets for the treatment of TCSCI. Lactobacillus was positively correlated with glucose levels. The dysbiosis of several key gut bacteria was associated with serum biomarkers of lipid metabolism in patients with TCSCI. The observed interdependency of the microbiota and lipid metabolism provides a basis for understanding the mechanisms underlying lipid disorders after cervical SCI.

The aim of this study was to estimate the effect of melatonin on spinal cord perfusion, the permeability of blood-spinal cord barrier (BSCB), and edema at the contusion epicenter and regions rostral and caudal to the injury site in rats with spinal cord injury (SCI). Thirty-six female Sprague-Dawley rats were divided into three groups (12 animals in each group): sham, SCI, and melatonin groups. Melatonin (50 mg/kg) was injected intraperitoneally at 30 min after a moderate injury at T10 in the melatonin group (twice a day). At 24 h postinjury, spinal cord perfusion was estimated using laser Doppler flowmetry, the permeability of BSCB was detected by Evan's blue, and edema was estimated by calculating the water content. A linear regression analysis was performed to assess the correlation between spinal cord perfusion and the permeability of BSCB or water content. Our results showed that melatonin significantly upregulated spinal cord blood flow and oxygen saturation in SCI rats using laser Doppler perfusion monitoring. Simultaneously, laser Doppler perfusion imaging indicated that melatonin markedly meliorated spinal cord perfusion in regions rostral and caudal to the injury site, rather than the epicenter site. Consistent with the results of laser Doppler flowmetry, melatonin significantly reduced the amount of Evan's blue dye and water content in regions of rostral and caudal cords. In addition, perfusion correlated with the permeability of BSCB and water content. These findings indicated that melatonin might exert a protective effect by meliorating microcirculation, which coordinated a corresponding response in the integrity of BSCB and edema.

Melatonin can be neuroprotective in models of neurological injury, but its effects on blood vessel loss and neurological impairment following spinal cord injury (SCI) are unclear. Our goal herein was to evaluate the possible protective action of melatonin on the above SCI-induced damage in rats.Sixty-three female Sprague-Dawley rats were randomly divided into three equal groups: sham, SCI and melatonin groups. Melatonin (10 mg/kg) was injected intraperitoneally and further administered twice a day at indicated time after a moderate injury at T10 in melatonin group. Blood vessel was assessed by CD31staining and FITC-LEA, the permeability of blood-spinal cord barrier (BSCB) was detected by Evan's Blue. Neuron was assessed by NeuN staining and the expression of Nissl bodies in the neurons was assessed by Nissl staining. The expressions of brain-derived neurotrophic factor (BDNF), synapsin I, or growth associated protein-43 (GAP-43) in the spinal cord and hippocampus were evaluated by Western blotting.At 7 days post-injury, melatonin treatment rescued blood vessels, increased CD31 levels, ameliorated BSCB permeability. Additionally, melatonin significantly increased the number of neurons and the expression of Nissl bodies in neurons at the injury epicenter. Furthermore, our data showed that SCI reduced levels of the molecular substrates of neurological plasticity, including BDNF, synapsin I, or GAP-43 in the spinal cord and hippocampus. Melatonin treatment partially prevented these reductions.The neuroprotective effect of melatonin was associated with melioration of the microcirculation in the spinal cord and reduction of neurological impairment in the spinal cord and brain.

Background Spinal cord injury (SCI) disturbs the autonomic nervous system and induces dysfunction or failure of multiple organs. The systemic microcirculation disturbance that contributes to the complications associated with SCI remains to be clarified. Methods We used male mice (29–32 g) and modified weight-drop injury at T10 to evaluate the systemic microcirculation dysfunction during the first 2 weeks after SCI. We determined permeability and microvascular blood flow in several organs and evaluated their vasomotor function. We also measured circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPCs), circulating pericyte progenitor cells (CPPCs), and serum proinflammatory cytokines. Results The endothelial permeability of almost all organs increased after SCI. Microvascular blood flow decreased in the bladder and kidney and increased in the spleen and was accompanied by endothelial vasomotor dysfunction. SCI also induced an increase in CECs, CEPCs, and CPPCs in peripheral blood. Finally, we confirmed changes in a systemic cytokine profile (interleukin [IL]-3, IL-6, IL-10, IL-13, granulocyte colony-stimulating factor, and regulated on activation normal T cell expressed and secreted) after SCI. Conclusions These data indicate that a systemic microcirculation disturbance occurs after SCI. This information may play a key role in the development of effective therapeutic strategies for SCI.

Laser Doppler flowmetry (LDF) is a noninvasive method for blood flow (BF) measurement, which makes it preferable for measuring microcirculatory alterations of the spinal cord. In this article, our goal was to use both Laser Doppler imaging and monitoring to analyze the change of BF after spinal cord injury. Both the laser Doppler image scanner and the probe/monitor were being employed to obtain each readout. The data of LDPI provided a local distribution of BF, which gave an overview of perfusion around the injury site and made it accessible for comparative analysis of BF among different locations. By intensely measuring the probing area over a period of time, a combined probe was used to simultaneously measure the BF and oxygen saturation of the spinal cord, showing overall spinal cord perfusion and oxygen supply. LDF itself has a few limitations, such as relative flux, sensitivity to movement, and biological zero signal. However, the technology has been applied in clinical and experimental study due to its simple setup and rapid measurement of BF.

Pericytes are contractile cells that wrap around the endothelial cells of capillaries throughout the body. They play an important role in regulating the blood brain barrier (BBB) and blood spinal cord barrier (BSCB). The differences between brain and spinal cord microvascular endothelial cells have been investigated. However, no report has elucidated the similarities and differences between brain microvascular pericytes (BMPs) and spinal cord microvascular pericytes (SCMPs) in vitro. The similarities were found between the two types of pericytes not only in the proliferation ability but also in the expression of toll like receptor 4. On the other hand, BMPs showed more than 2 fold in tubular length formation compared with SCMPs. The number of migratory SCMPs was larger than that of migratory BMPs. The expressions of connexin 43 and vascular endothelial growth factor (VEGF) in BMPs were increased compared with those in SCMPs, while SCMPs expressed more desmin and N-cadherin than BMPs. The abilities of tube-formation and migration between BMPs and SCMPs were markedly different, which might be mediated by VEGF, connexin 43, N-cadherin and desmin. These distinguishing features may reflect the more widespread differences between the BBB and BSCB which directly impact pathophysiological processes in various major diseases.

Spinal cord injury (SCI) can promote profound functional modification in various brain centers. However, the question of whether SCI can affect the generation of silent synapses that regulate neuronal plasticity in the hippocampus remains unclear. In the present studies, we demonstrated that acute SCI diminished silent synapses in hippocampus of lesioned rats. Furthermore, the SCI induced decline in silent synapses appeared to require the activation of NR2B-containing N-methyl-D-aspartate receptors. Our data show that SCI impaired synaptic plasticity in the hippocampus, suggesting that this region may serve as a potential therapeutic target for meliorating impaired brain functions after SCI.

The spinal cord microcirculation plays a critically important role in maintaining the normal function of spinal cord neurons, glial cells, and axons. Previous researches were largely focused on improved neurological manifestations of spinal cord injury (SCI) while ignoring to improve spinal cord microcirculation disorder after melatonin treatment. Therefore, the mechanism of melatonin that affects blood spinal cord barrier (BSCB) integrity and microcirculation in SCI remains unclear. The present study was performed to investigate the effect of melatonin on the BSCB in a SCI mice model. Melatonin (5, 10, 25, 50, 100 mg/kg i.p.) was administered to mice immediately following SCI. Compared to the 48 h post-SCI group, mice treated with melatonin (50 mg/kg) exhibited significantly reduced BSCB permeability. Additionally, melatonin treatment restrained microvessel loss; attenuated edema; protected the tight junction proteins, endothelial cells, and pericytes; decreased the number of cell apoptosis; and reduced MMP3/AQP4/HIF-1α/VEGF/VEGFR2 expression after SCI. Above all, our results clearly demonstrated that melatonin could stabilize microvascular barrier function and microcirculation of SCI, whose mechanism was to promote the repair of the damaged BSCB.