C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

Biochanin A attenuates spinal cord injury in rats during early stages by inhibiting oxidative stress and inflammasome activation

Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord injury is still unclea r. In this study,a rat model of spinal cord injury was established using the heavy o bject impact method,and the rats were then treated with Biochanin A(40 mg/kg) via intrape ritoneal injection for 14 consecutive days.The res ults showed that Biochanin A effectively alleviated spinal cord neuronal injury and spinal co rd tissue injury,reduced inflammation and oxidative stress in spinal cord neuro ns,and reduced apoptosis and pyroptosis.In addition,Biochanin A inhibited the expression of inflammasome-related proteins(ASC,NLRP3,and GSDMD)and the Toll-like receptor 4/nuclear factor-κB pathway,activated the Nrf2/heme oxygenase 1 signaling pathway,and increased the expression of the autophagy markers LC3 Ⅱ,Beclin-1,and P62.Moreove r,the therapeutic effects of Biochanin A on early post-s pinal cord injury were similar to those of methylprednisolone.These findings suggest that Biochanin A protected neurons in the injured spinal cord through the Toll-like receptor 4/nuclear factor κB and Nrf2/heme oxygenase 1 signaling pathways.These findings suggest that Biochanin A can alleviate post-spinal cord injury at an early stage.

Dual-directional regulation of spinal cord injury and the gut microbiota

There is increasing evidence that the gut microbiota affects the incidence and progression of central nervous system diseases via the brain-gut axis.The spinal cord is a vital important part of the central nervous system;however,the underlying association between spinal cord injury and gut interactions remains unknown.Recent studies suggest that patients with spinal cord injury frequently experience intestinal dysfunction and gut dysbiosis.Alterations in the gut microbiota can cause disruption in the intestinal barrier and trigger neurogenic inflammatory responses which may impede recovery after spinal cord injury.This review summarizes existing clinical and basic research on the relationship between the gut microbiota and spinal cord injury.Our research identified three key points.First,the gut microbiota in patients with spinal cord injury presents a key characteristic and gut dysbiosis may profoundly influence multiple organs and systems in patients with spinal cord injury.Second,following spinal cord injury,weakened intestinal peristalsis,prolonged intestinal transport time,and immune dysfunction of the intestine caused by abnormal autonomic nerve function,as well as frequent antibiotic treatment,may induce gut dysbiosis.Third,the gut microbiota and associated metabolites may act on central neurons and affect recovery after spinal cord injury;cytokines and the Toll-like receptor ligand pathways have been identified as crucial mechanisms in the communication between the gut microbiota and central nervous system.Fecal microbiota transplantation,probiotics,dietary interventions,and other therapies have been shown to serve a neuroprotective role in spinal cord injury by modulating the gut microbiota.Therapies targeting the gut microbiota or associated metabolites are a promising approach to promote functional recovery and improve the complications of spinal cord injury.

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

The role of purinergic receptors in neural repair and regeneration after spinal cord injury

Spinal cord injury is a serious injury of the central nervous system that results in neurological deficits.The pathophysiological mechanisms underlying spinal cord injury,as well as the mechanisms involved in neural repair and regeneration,are highly complex.Although there have been many studies on these mechanisms,there is no effective intervention for such injury.In spinal cord injury,neural repair and regeneration is an important part of improving neurological function after injury,although the low regenerative ability of nerve cells and the difficulty in axonal and myelin regeneration after spinal cord injury hamper functional recovery.Large amounts of ATP and its metabolites are released after spinal cord injury and participate in various aspects of functional regulation by acting on purinergic receptors which are widely expressed in the spinal cord.These processes mediate intracellular and extracellular signalling pathways to improve neural repair and regeneration after spinal cord injury.This article reviews research on the mechanistic roles of purinergic receptors in spinal cord injury,highlighting the potential role of purinergic receptors as interventional targets for neural repair and regeneration after spinal cord injury.

Eph receptor A4 regulates motor neuron ferroptosis in spinal cord ischemia/reperfusion injury in rats

Previous studies have shown that the receptor tyrosine kinase Eph receptor A4(EphA4) is abundantly expressed in the nervous system. The EphA4 signaling pathway plays an important role in regulating motor neuron ferroptosis in motor neuron disease. To investigate whether EphA4 signaling is involved in ferroptosis in spinal cord ischemia/reperfusion injury, in this study we established a rat model of spinal cord ischemia/reperfusion injury by clamping the left carotid artery and the left subclavian artery. We found that spinal cord ischemia/reperfusion injury increased EphA4 expression in the neurons of anterior horn, markedly worsened ferroptosis-related indicators, substantially increased the number of mitochondria exhibiting features consistent with ferroptosis, promoted deterioration of motor nerve function, increased the permeability of the blood-spinal cord barrier, and increased the rate of motor neuron death. Inhibition of EphA4 largely rescued these effects. However, intrathecal administration of the ferroptosis inducer Erastin counteracted the beneficial effects conferred by treatment with the EphA4 inhibitor. Mass spectrometry and a PubMed search were performed to identify proteins that interact with EphA4, with the most notable being Beclin1 and Erk1/2. Our results showed that inhibition of EphA4 expression reduced binding to Beclin1, markedly reduced p-Beclin1, and reduced Beclin1-XCT complex formation. Inhibition of EphA4 also reduced binding to p-Erk1/2 and markedly decreased the expression of c-Myc, transferrin receptor 1, and p-Erk1/2. Additionally, we observed co-localization of EphA4 and p-Beclin1 and of EphA4 and p-ERK1/2 in neurons in the anterior horn. In conclusion, EphA4 participates in regulating ferroptosis of spinal motor neurons in the anterior horn in spinal cord ischemia/reperfusion injury by promoting formation of the Beclin1-XCT complex and activating the Erk1/2/c-Myc/transferrin receptor 1 axis.

Future directions for using estrogen receptor agonists in the treatment of acute and chronic spinal cord injury

All synthetic and natural estrogen receptor agonists, in- cluding the most potent physiological molecule estrogen or estradiol （E2）, work typically via activation of nuclear estrogen receptor alpha （ERα） and estrogen receptor beta （ERβ）. Both ERα and ERβ modulate the expression of a variety of genes in the cells. Neurons and glial cells express ERa and ERβ. Many studies so far from our and other laboratories have firmly established the mode of actions that ERα and ERβ agonists are very promising anti-inflammatory and neuroprotective agents in the treatment of neurodegenera- rive diseases and injuries including spinal cord injury （SCI） （Chakrabarti et al., 2014a）.

Microglial depletion impairs glial scar formation and aggravates inflammation partly by inhibiting STAT3 phosphorylation in astrocytes after spinal cord injury

Astrocytes and microglia play an orchestrated role following spinal cord injury;however,the molecular mechanisms through which microglia regulate astrocytes after spinal cord injury are not yet fully understood.Herein,microglia were pharmacologically depleted and the effects on the astrocytic response were examined.We further explored the potential mechanisms involving the signal transducers and activators of transcription 3(STAT3)pathway.For in vivo experiments,we constructed a contusion spinal cord injury model in C57BL/6 mice.To deplete microglia,all mice were treated with colony-stimulating factor 1 receptor inhibitor PLX3397,starting 2 weeks prior to surgery until they were sacrificed.Cell proliferation was examined by 5-ethynyl-2-deoxyuridine(EdU)and three pivotal inflammatory cytokines were detected by a specific Bio-Plex Pro^(TM) Reagent Kit.Locomotor function,neuroinflammation,astrocyte activation and phosphorylated STAT3(pSTAT3,a maker of activation of STAT3 signaling)levels were determined.For in vitro experiments,a microglia and astrocyte coculture system was established,and the small molecule STA21,which blocks STAT3 activation,was applied to investigate whether STAT3 signaling is involved in mediating astrocyte proliferation induced by microglia.PLX3397 administration disrupted glial scar formation,increased inflammatory spillover,induced diffuse tissue damage and impaired functional recovery after spinal cord injury.Microglial depletion markedly reduced EdU+proliferating cells,especially proliferating astrocytes at 7 days after spinal cord injury.RNA sequencing analysis showed that the JAK/STAT3 pathway was downregulated in mice treated with PLX3397.Double immunofluorescence staining confirmed that PLX3397 significantly decreased STAT3 expression in astrocytes.Importantly,in vitro coculture of astrocytes and microglia showed that microglia-induced astrocyte proliferation was abolished by STA21 administration.These findings suggest that microglial depletion impaired astrocyte proliferation and astrocytic scar formation,and induced inflammatory diffusion partly by inhibiting STAT3 phosphorylation in astrocytes following spinal cord injury.

Multiomics reveal human umbilical cord mesenchymal stem cells improving acute lung injury via the lung-gut axis

BACKGROUND Acute lung injury(ALI)and its final severe stage,acute respiratory distress syndrome,are associated with high morbidity and mortality rates in patients due to the lack of effective specific treatments.Gut microbiota homeostasis,including that in ALI,is important for human health.Evidence suggests that the gut microbiota improves lung injury through the lung-gut axis.Human umbilical cord mesenchymal cells(HUC-MSCs)have attractive prospects for ALI treatment.This study hypothesized that HUC-MSCs improve ALI via the lung-gut microflora.AIM To explore the effects of HUC-MSCs on lipopolysaccharide(LPS)-induced ALI in mice and the involvement of the lung-gut axis in this process.METHODS C57BL/6 mice were randomly divided into four groups(18 rats per group):Sham,sham+HUC-MSCs,LPS,and LPS+HUC-MSCs.ALI was induced in mice by intraperitoneal injections of LPS(10 mg/kg).After 6 h,mice were intervened with 0.5 mL phosphate buffered saline(PBS)containing 1×10^(6) HUC-MSCs by intraperitoneal injections.For the negative control,100 mL 0.9%NaCl and 0.5 mL PBS were used.Bronchoalveolar lavage fluid(BALF)was obtained from anesthetized mice,and their blood,lungs,ileum,and feces were obtained by an aseptic technique following CO_(2) euthanasia.Wright’s staining,enzyme-linked immunosorbent assay,hematoxylin-eosin staining,Evans blue dye leakage assay,immunohistochemistry,fluorescence in situ hybridization,western blot,16S rDNA sequencing,and non-targeted metabolomics were used to observe the effect of HUC-MSCs on ALI mice,and the involvement of the lung-gut axis in this process was explored.One-way analysis of variance with post-hoc Tukey’s test,independent-sample Student’s t-test,Wilcoxon rank-sum test,and Pearson correlation analysis were used for statistical analyses.RESULTS HUC-MSCs were observed to improve pulmonary edema and lung and ileal injury,and decrease mononuclear cell and neutrophil counts,protein concentrations in BALF and inflammatory cytokine levels in the serum,lung,and ileum of ALI mice.Especially,HUC-MSCs decreased Evans blue concentration and Toll-like receptor 4,myeloid differentiation factor 88,p-nuclear factor kappa-B(NF-κB)/NF-κB,and p-inhibitorαof NF-κB(p-IκBα)/IκBαexpression levels in the lung,and raised the pulmonary vascular endothelial-cadherin,zonula occludens-1(ZO-1),and occludin levels and ileal ZO-1,claudin-1,and occludin expression levels.HUC-MSCs improved gut and BALF microbial homeostases.The number of pathogenic bacteria decreased in the BALF of ALI mice treated with HUCMSCs.Concurrently,the abundances of Oscillospira and Coprococcus in the feces of HUS-MSC-treated ALI mice were significantly increased.In addition,Lactobacillus,Bacteroides,and unidentified_Rikenellaceae genera appeared in both feces and BALF.Moreover,this study performed metabolomic analysis on the lung tissue and identified five upregulated metabolites and 11 downregulated metabolites in the LPS+MSC group compared to the LPS group,which were related to the purine metabolism and the taste transduction signaling pathways.Therefore,an intrinsic link between lung metabolite levels and BALF flora homeostasis was established.CONCLUSION This study suggests that HUM-MSCs attenuate ALI by redefining the gut and lung microbiota.

Protective effect of thodioloside and bone marrow mesenchymal stem cells infected with HIF-1-expressing adenovirus on acute spinal cord injury

Rhodioloside has been shown to protect cells from hypoxia injury,and bone marrow mesenchymal stem cells have a good effect on tissue repair.To study the effects of rhodioloside and bone marrow mesenchymal stem cells on spinal cord injury,a rat model of spinal cord injury was established using the Infinite Horizons method.After establishing the model,the rats were randomly divided into five groups.Rats in the control group were intragastrically injected with phosphate buffered saline(PBS)(5μL).PBS was injected at 6 equidistant points around 5 mm from the injury site and at a depth of 5 mm.Rats in the rhodioloside group were intragastrically injected with rhodioloside(5 g/kg)and intramuscularly injected with PBS.Rats in the mesenchymal stem cell(MSC)group were intramuscularly injected with PBS and intramuscularly with MSCs(8×10^6/mL in a 50-μL cell suspension).Rats in the Ad-HIF-MSC group were intragastrically injected with PBS and intramuscularly injected with HIF-1 adenovirus-infected MSCs.Rats in the rhodioloside+Ad-HIF-MSC group were intramuscularly injected with MSCs infected with the HIF-1 adenovirus and intragastrically injected with rhodioloside.One week after treatment,exercise recovery was evaluated with a modified combined behavioral score scale.Hematoxylin-eosin staining and Pischingert’s methylene blue staining were used to detect any histological or pathological changes in spinal cord tissue.Levels of adenovirus IX and Sry mRNA were detected by real-time quantitative polymerase chain reaction and used to determine the number of adenovirus and mesenchymal stem cells that were transfected into the spinal cord.Immunohistochemical staining was applied to detect HIF-1 protein levels in the spinal cord.The results showed that:(1)compared with the other groups,the rhodioloside+Ad-HIF-MSC group exhibited the highest combined behavioral score(P<0.05),the most recovered tissue,and the greatest number of neurons,as indicated by Pischingert’s methylene blue staining.(2)Compared with the PBS group,HIF-1 protein expression was greater in the rhodioloside group(P<0.05).(3)Compared with the Ad-HIF-MSC group,Sry mRNA levels were higher in the rhodioloside+Ad-HIF-MSC group(P<0.05).These results confirm that rhodioloside combined with bone marrow mesenchymal stem cells can promote the recovery of spinal cord injury and activate the HIF-1 pathway to promote the survival of bone marrow mesenchymal stem cells and repair damaged neurons within spinal cord tissue.This experiment was approved by the Animal Ethics Committee of Gansu University of Traditional Chinese Medicine,China(approval No.2015KYLL029)in June 2015.

Transplantation of Nogo-66 receptor gene-silenced cells in a poly(D,L-lactic-co-glycolic acid) scaffold for the treatment of spinal cord injury

Inhibition of neurite growth, which is in large part mediated by the Nogo-66 receptor, affects neural regeneration following bone marrow mesenchymal stem cell transplantation. The tissue engineering scaffold poly（D,L-lactide-co-glycolic acid） has good histocompatibility and can promote the growth of regenerating nerve fibers. The present study used small interfering RNA to silence Nogo-66 receptor gene expression in bone marrow mesenchymal stem cells and Schwann cells, which were subsequently transplanted with poly（D,L-lactide-co-glycolic acid） into the spinal cord lesion regions in rats. Simultaneously, rats treated with scaffold only were taken as the control group. Hematoxylin-eosin staining and immunohistochemistry revealed that at 4 weeks after transplantation, rats had good motor function of the hind limb after treatment with Nogo-66 receptor gene-silenced ceils prus the poly（O,L-lactide-co-glycolic acid） scaffold compared with rats treated with scaffold only, and the number of bone marrow mesenchymal stem cells and neuron-like cells was also increased. At 8 weeks after transplantation, horseradish peroxidase tracing and transmission electron microscopy showed a large number of unmyelinated and myelinated nerve fibers, as well as intact regenerating axonal myelin sheath following spinal cord hemisection injury. These experimental findings indicate that transplantation of Nogo-66 receptor gene-silenced bone marrow mesenchymal stem cells and Schwann cells plus a poly（D,L-lactide-co-glycolic acid） scaffold can significantly enhance axonal regeneration of spinal cord neurons and improve motor function of the extremities in rats following spinal cord injury.

Dose optimization of intrathecal administration of human umbilical cord mesenchymal stem cells for the treatment of subacute incomplete spinal cord injury

Human umbilical cord mesenchymal stem cells(hUC-MSCs)are a promising candidate for spinal cord injury(SCI)repair owing to their advantages of low immunogenicity and easy accessibility over other MSC sources.However,modest clinical efficacy hampered the progression of these cells to clinical translation.This discrepancy may be due to many variables,such as cell source,timing of implantation,route of administration,and relevant efficacious cell dose,which are critical factors that affect the efficacy of treatment of patients with SCI.Previously,we have evaluated the safety and efficacy of 4×10^(6) hUC-MSCs/kg in the treatment of subacute SCI by intrathecal implantation in rat models.To search for a more accurate dose range for clinical translation,we compared the effects of three different doses of hUC-MSCs-low(0.25×10^(6) cells/kg),medium(1×10^(6) cells/kg)and high(4×10^(6) cells/kg)-on subacute SCI repair through an elaborate combination of behavioral analyses,anatomical analyses,magnetic resonance imaging-diffusion tensor imaging(MRI-DTI),biotinylated dextran amine(BDA)tracing,electrophysiology,and quantification of mRNA levels of ion channels and neurotransmitter receptors.Our study demonstrated that the medium dose,but not the low dose,is as efficient as the high dose in producing the desired therapeutic outcomes.Furthermore,partial restoration of theγ-aminobutyric acid type A(GABAA)receptor expression by the effective doses indicates that GABAA receptors are possible candidates for therapeutic targeting of dormant relay pathways in injured spinal cord.Overall,this study revealed that intrathecal implantation of 1×10^(6) hUC-MSCs/kg is an alternative approach for treating subacute SCI.

Factors related to improved American Spinal Injury Association grade of acute traumatic spinal cord injury

BACKGROUND Acute traumatic spinal cord injury(ATSCI)usually results in disability,yet data on contemporary national trends of ATSCI incidence are limited.AIM To provide a systematic and basic theoretical basis for improving the treatment of acute spinal cord injury.METHODS Data from the Peking University Third Hospital Inpatient Sample databases were analyzed.A total of 304 patients with ATSCI were included from 2012 to 2017.The epidemiological data,treatment,complications and clinical outcomes of these patients were reviewed.RESULTS Of the 304 patients,257(84.5%)were male,and 75%of the patients were 55 years old or younger.135 patients had improved follow-up American Spinal Injury Association(ASIA)grades(44.4%).Only 14 patients with ASIA grade A improved.A statistically significant difference in prognosis between patients who underwent surgery within 72 h and those who underwent surgery after 72 h was observed(P<0.05).Surgery within 72 h resulted in better prognosis.The Steroid group and the Non-Steroid group showed a significant difference in outcome among patients with ASIA grades A and B(P<0.05).Patients with pneumonia had a poorer prognosis than patients without pneumonia(P<0.05).Surgery within 72 h resulted in better prognosis.CONCLUSION This study found that there was no significant difference in hospitalization time and prognosis between the Steroid group and the Non-Steroid group,but the patients with severe spinal cord injury(ASIA grades A and B)who underwent surgery combined with steroid therapy had a better prognosis than those who underwent surgery alone.The disastrous consequences of ATSCI and lack of consensus on the management strategy are obvious.Further improvements in treatment planns are needed in order to obtain more reliable functional outcomes.

Effects of decompression joint Governor Vessel electro-acupuncture on rats with acute upper cervical spinal cord injury

Decompression is the major therapeutic strategy for acute spinal cord injury,but there is some debate about the time window for decompression following spinal cord injury.An important goal and challenge in the treatment of spinal cord injury is inhibiting or reversing secondary injury.Governor Vessel electroacupuncture can improve symptoms of spinal cord injury by inhibiting cell apoptosis and improving the microenvironment of the injured spinal cord.In this study,Governor Vessel electroacupuncture combined with decompression at different time points was used to treat acute spinal cord injury.The rat models were established by inserting a balloon catheter into the atlanto-occipital space.The upper cervical spinal cord was compressed for 12 or 48 hours prior to decompression.Electroacupuncture was conducted at the acupoints Dazhui（GV14） and Baihui（GV 20）（2 Hz,15 minutes） once a day for 14 consecutive days.Compared with decompression alone,hind limb motor function recovery was superior after decompression for 12 and 48 hours combined with electroacupuncture.However,the recovery of motor function was not significantly different at 14 days after treatment in rats receiving decompression for 12 hours.Platelet-activating factor levels and caspase-9 protein expression were significantly reduced in rats receiving electroacupuncture compared with decompression alone.These findings indicate that compared with decompression alone,Governor Vessel electroacupuncture combined with delayed decompression（48 hours） is more effective in the treatment of upper cervical spinal cord injury.Governor Vessel electroacupuncture combined with early decompression（12 hours） can accelerate the recovery of nerve movement in rats with upper cervical spinal cord injury.Nevertheless,further studies are necessary to confirm whether it is possible to obtain additional benefit compared with early decompression alone.

Bone marrow mesenchymal stem cells with Nogo-66 receptor gene silencing for repair of spinal cord injury

We hypothesized that RNA interference to silence Nogo-66 receptor gene expression in bone marrow mesenchymal stem cells before transplantation might further improve neurological function in rats with spinal cord transection injury. After 2 weeks, the number of neurons and BrdU-positive cells in the Nogo-66 receptor gene silencing group was higher than in the bone marrow mesenchymal stem cell group, and significantly greater compared with the model group. After 4 weeks, behavioral performance was signiifcantly enhanced in the model group. Af-ter 8 weeks, the number of horseradish peroxidase-labeled nerve ifbers was higher in the Nogo-66 receptor gene silencing group than in the bone marrow mesenchymal stem cell group, and signiifcantly higher than in the model group. The newly formed nerve ifbers and myelinated ner ve ifbers were detectable in the central transverse plane section in the bone marrow mesenchymal stem cell group and in the Nogo-66 receptor gene silencing group.

Management of acute spinal cord injury:A summary of the evidence pertaining to the acute management,operative and non-operative management

Acute traumatic spinal cord injury is often a lifechanging and devastating event with considerable mortality and morbidity.Over half a million people suffer from traumatic spinal cord injury annually with the majority resulting from road traffic accidents or falls.The Individual,societal and economic costs are enormous.Initial recognition and treatment of acute traumatic spinal cord injury are crucial to limit secondary injury to the spinal cord and to provide patients with the best chance of some functional recovery.This article is an overview of the management of the acute traumatic spinal cord injury patient presenting to the emergency department.We review the initial assessment,criteria for imaging and clearing the spine,and evaluate the literature to determine the optimum timing of surgery and the role of non-surgical treatment in patients presenting with acute spinal cord injury.

Influence of tanshinone on N-methyl-D-aspartate receptor 1 protein expression in a rat model of spinal cord ischemia/reperfusion injury

BACKGROUND： Tanshinone has been previously shown to be involved in the prevention and treatment of cerebral ischemia/reperfusion injury. In addition, excitatory amino acid-mediated neu- rotoxicity may induce neuronal damage following spinal cord ischemia/reperfusion injury. OBJECTIVE： To explore the interventional effect of tanshinone on N-methyl-D-aspartate receptor 1 （NMDAR1） protein expression in a rat model of spinal cord ischemia/reperfusion injury. DESIGN, TIME AND SETTING： A randomized molecular biology experiment was conducted at the Traumatology ＆ Orthopedics Laboratory of Fujian Hospital of Traditional Chinese Medicine （Key Laboratory of State Administration of Traditional Chinese Medicine） between September 2007 and May 2008. MATERIALS： A total of 88 Sprague Dawley rats were randomly divided into a sham operation （n = 8）, model （n = 40）, and tanshinone （n = 40） groups. Thirty minutes after ischemia, rats in the model and tanshinone groups were observed at hour 0.5, 1, 4, 8, and 12 following perfusion, with eight rats for each time point. METHODS： Abdominal aorta occlusion was performed along the right renal arterial root using a Scoville-Lewis clamp to induce spinal cord ischemia. Blood flow was recovered 30 minutes following occlusion to establish models of spinal cord ischemia/reperfusion injury. Abdominal aorta occlusion was not performed in the sham operation group. An intraperitoneal injection of tanshinone ⅡA sulfonic sodium solution （0.2 L/g） was administered to rats in the tanshinone group, preoperatively. In addition, rats in the sham operation and model groups were treated with an intraperitoneal injection of the same concentration of saline, preoperatively. MAIN OUTCOME MEASURES： NMDAR1 protein expression in the anterior horn of the spinal cord, accumulative absorbance, average absorbance, and area of positive cells were detected in the three groups through immunohistochemistry. RESULTS： All 88 rats were included in the final analysis. （1） NMDAR1 protein expression increased following 30-minute ischemia/1-hour reperfusion injury to the spinal cord, and reached a peak 4 hours after reperfusion. （2） Accumulative absorbance and average absorbance of NMDAR1, as well as area of positive cells in the model group, were significantly greater than the sham operation group at each time point （P 〈 0.05）. However, values in the tanshinone group were significantly less than the model group （P 〈 0.05）. CONCLUSION： NMDAR1 protein expression was rapidly increased following spinal cord ischemia/reperfusion injury and reached a peak 4 hours following reperfusion. In addition, tanshinone downregulated NMDAR1 protein expression in the anterior horn of the spinal cord.

Distribution of paired immunoglobulin-like receptor B in the nervous system related to regeneration difficulties after unilateral lumbar spinal cord injury

Paired immunoglobulin-like receptor B（Pir B） is a functional receptor of myelin-associated inhibitors for axonal regeneration and synaptic plasticity in the central nervous system, and thus suppresses nerve regeneration. The regulatory effect of Pir B on injured nerves has received a lot of attention. To better understand nerve regeneration inability after spinal cord injury, this study aimed to investigate the distribution of Pir B（via immunofluorescence） in the central nervous system and peripheral nervous system 10 days after injury. Immunoreactivity for Pir B increased in the dorsal root ganglia, sciatic nerves, and spinal cord segments. In the dorsal root ganglia and sciatic nerves, Pir B was mainly distributed along neuronal and axonal membranes. Pir B was found to exhibit a diffuse, intricate distribution in the dorsal and ventral regions. Immunoreactivity for Pir B was enhanced in some cortical neurons located in the bilateral precentral gyri. Overall, the findings suggest a pattern of Pir B immunoreactivity in the nervous system after unilateral spinal transection injury, and also indicate that Pir B may suppress repair after injury.

Methylprednisolone intrathecal injections suppress neuronal apoptosis following acute spinal cord injury

High dose methylprednisolone intravenous injections are effective in treating acute spinal cord injury but can have severe side effects. In this study, we investigated intrathecal delivery of methylprednisolone for the treatment of spinal cord injury. In particular, we examined the effects of varying doses of methylprednisolone intrathecal injections on neuronal apoptosis induced by secondary damage. The results demonstrate that intrathecal injections inhibit the expression of interleukin-lβ, significantly lower expression of caspase-3, and reduce the number of apoptotic neurons, High dose methylprednisolone （0.75 mg/μL） was much more effective at reducing neuronal apoptosis than low dose methvlprednisolone （0.01 ma/μL.

Early methylprednisolone impact treatment for sensory and motor function recovery in patients with acute spinal cord injury A self-control study

BACKGROUND： For the treatment of spinal cord injury, any pathological changes of the injured tissue should be primarily corrected or reversed. Any remaining fibrous function and neurons with intact structure should be retained, and the toxic substances caused by ischemia-hypoxia following spinal cord injury, should be eliminated to create a favorable environment that would promote neural functional recovery. OBJECTIVE： This study was designed to investigate the effects of the impact of early methylprednisolone-treatment on the sensory and motor function recovery in patients with acute spinal cord injury. DESIGN： A self-control observation. SETTING： Department of Spine Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China. PARTICIPANTS： Forty-three patients with acute spinal cord injury were admitted to the Department of Spine Surgery, First Affiliated Hospital of Nanjing Medical University, between October 2005 and September 2007. These patients were recruited for the present study. The patients comprised 33 males and 10 females, and all met with the inclusive criteria namely, the time between suffering from acute spinal cord injury and receiving treatment was less than or equal to eight hours. METHODS： According to the protocol determined by the State Second Conference of Acute Spinal Cord Injury of USA, all patients received the drop-wise administration of a 30-mg/kg dose of methylprednisolone （H200040339, 500 mg/bottle, Pharmacia N.V/S.A, Belgium） for 15 minutes within 8 hours post injury. After a 45-minute interval, methylprednisolone was administered at 5.4 mg/kg/h for 23 hours. MAIN OUTCOME MEASURES： Prior to and post treatment, acupuncture sense and light touch scoring were performed at 28 dermatomic area key points, including occipital tuberosity and supraclavicular fossa. At the same time, motor scoring of key muscles among 10 pairs of sarcomeres was also performed. RESULTS： All 43 patients participated in the final analysis. There was no significant difference of sensory and motor scores in patients with complete acute spinal cord injury between prior to and post methylprednisolone impact treatment （P 〉 0.05）. The motor score was significantly decreased in patients with incomplete acute spinal cord injury post methylprednisolone impact treatment （P 〈 0.01 ）. CONCLUSION： Early methylprednisolone impact may improve the motor function of patients with incomplete acute spinal cord injury. However, it has no influences on patients with complete acute spinal cord injury.