Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience.The function of the neural pathway under the damaged sites can be rebuilt using functio...Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience.The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology.In this study,the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology.A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn.Based on the individual experimental parameters and normalized coordinates of the motor function sites,the motor function sites that control a certain muscle were calculated.Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension,hip flexion,ankle plantarflexion,and ankle dorsiflexion movements were successfully achieved.The results show that the map of the spinal cord motor function sites was valid.This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury.展开更多
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 b...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.展开更多
Objective:Studies have shown that docosahexaenoic acid(DHA)has a beneficial effect in the treatment of spinal cord injury.A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spi...Objective:Studies have shown that docosahexaenoic acid(DHA)has a beneficial effect in the treatment of spinal cord injury.A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spinal cord injury model,and the relationship between the recovery of motor function after spinal cord injury and the time and method of administration and the dose of DHA.Data source:Published studies on the effect of DHA on spinal cord injury animal models from seven databases were searched from their inception to January 2019,including PubMed,MEDLINE,EMBASE,the China National Knowledge Infrastructure,Wanfang,VIP,and SinoMed databases.The search terms included“spinal cord injury”“docosahexaenoic acid”,and“rats”.Data selection:Studies that evaluated the influence of DHA in rat models of spinal cord injury for locomotor functional recovery were included.The intervention group included any form of DHA treatment and the control group included treatment with normal saline,vehicle solution or no treatment.The Systematic Review Centre for Laboratory animal Experimentation’s risk of bias assessment tool was used for the quality assessment of the included studies.Literature inclusion,quality evaluation and data extraction were performed by two researchers.Meta-analysis was then conducted on all studies that met the inclusion criteria.Statistical analysis was performed on the data using RevMan 5.1.2.software.Outcome measures:The primary outcome measure was the score on the Basso,Beattie,and Bresnahan scale.Secondary outcome measures were the sloping plate test,balance beam test,stair test and grid exploration test.Results:A total of 12 related studies were included,3 of which were of higher quality and the remaining 9 were of lower quality.The highest mean Basso,Beattie,and Bresnahan scale score occurred at 42 days after DHA treatment in spinal cord injury rats.At 21 days after treatment,the mean difference in Basso,Beattie,Bresnahan scores between the DHA group and the control group was the most significant(pooled MD=4.14;95%CI=3.58–4.70;P<0.00001).In the subgroup analysis,improvement in the Basso,Beattie,and Bresnahan scale score was more significant in rats administered DHA intravenously(pooled MD=2.74;95%CI=1.41–4.07;P<0.0001)and subcutaneously(pooled MD=2.99;95%CI=2.29–3.69;P<0.00001)than in the groups administered DHA orally(pooled MD=3.04;95%CI=–1.01 to 7.09;P=0.14).Intravenous injection of DHA at 250 nmol/kg(pooled MD=2.94;95%CI=2.47–3.41;P<0.00001]and 1000 nmol/kg[pooled MD=3.60;95%CI=2.66–4.54;P<0.00001)significantly improved the Basso,Beattie,and Bresnahan scale score in rats and promoted the recovery of motor function.Conclusion:DHA can promote motor functional recovery after spinal cord injury in rats.The administration of DHA by intravenous or subcutaneous injection is more effective than oral administration of DHA.Intravenous injection of DHA at doses of 250 nmol/kg or 1000 nmol/kg is beneficial.Because of the small number and the low quality of the included studies,more high-quality research is needed in future to substantiate the results.展开更多
The repair effects of bone marrow mesenchymal stem cell transplantation on nervous system damage are not satisfactory. Propofol has been shown to protect against spinal cord injury. Therefore, this study sought to exp...The repair effects of bone marrow mesenchymal stem cell transplantation on nervous system damage are not satisfactory. Propofol has been shown to protect against spinal cord injury. Therefore, this study sought to explore the therapeutic effects of their combination on spinal cord injury. Rat models of spinal cord injury were established using the weight drop method. Rats were subjected to bone marrow mesenchymal stem cell transplantationvia tail vein injection and/or propofol injectionvia tail vein using an infusion pump. Four weeks after cell transplan-tation and/or propofol treatment, the cavity within the spinal cord was reduced. The numbers of PKH-26-positive cells and horseradish peroxidase-positive nerve ifbers apparently increased in the spinal cord. Latencies of somatosensory evoked potentials and motor evoked potentials in the hindlimb were noticeably shortened, amplitude was increased and hindlimb motor function was obviously improved. Moreover, the combined effects were better than cell transplantation or propofol injection alone. The above data suggest that the combination of propofol injection and bone marrow mesenchymal stem cell transplantation can effectively improve hindlimb electro-physiological function, promote the recovery of motor funtion, and play a neuroprotective role in spinal cord injury in rats.展开更多
Senegenin has been shown to inhibit neuronal apoptosis,thereby exerting a neuroprotective effect.In the present study,we established a rat model of spinal cord contusion injury using the modified Allen＇s method.Three...Senegenin has been shown to inhibit neuronal apoptosis,thereby exerting a neuroprotective effect.In the present study,we established a rat model of spinal cord contusion injury using the modified Allen＇s method.Three hours after injury,senegenin（30 mg/g） was injected into the tail vein for 3 consecutive days.Senegenin reduced the size of syringomyelic cavities,and it substantially reduced the number of apoptotic cells in the spinal cord.At the site of injury,Bax and Caspase-3 m RNA and protein levels were decreased by senegenin,while Bcl-2 m RNA and protein levels were increased.Nerve fiber density was increased in the spinal cord proximal to the brain,and hindlimb motor function and electrophysiological properties of rat hindlimb were improved.Taken together,our results suggest that senegenin exerts a neuroprotective effect by suppressing neuronal apoptosis at the site of spinal cord injury.展开更多
Clinical studies have shown that hyperbaric oxygen therapy improves motor function in patients with spinal cord injury. In the present study, we explored the mechanisms associated with the recovery of neurological fun...Clinical studies have shown that hyperbaric oxygen therapy improves motor function in patients with spinal cord injury. In the present study, we explored the mechanisms associated with the recovery of neurological function after hyperbaric oxygen therapy in a rat model of spinal cord injury. We established an acute spinal cord injury model using a modification of the free-falling object method, and treated the animals with oxygen at 0.2 MPa for 45 minutes, 4 hours after injury. The treatment was administered four times per day, for 3 days. Compared with model rats that did not receive the treatment, rats exposed to hyperbaric oxygen had fewer apoptotic cells in spinal cord tissue, lower expression levels of aquaporin 4/9 mRNA and protein, and more NF-200 positive nerve fibers. Furthermore, they had smaller spinal cord cavities, rapid recovery of somatosensory and motor evoked potentials, and notably better recovery of hindlimb motor function than model rats. Our findings indicate that hyperbaric oxygen therapy reduces apoptosis, downregulates aquaporin 4/9 mRNA and protein expression in injured spinal cord tissue, improves the local microenvironment for nerve regeneration, and protects and repairs the spinal cord after injury.展开更多
Repetitive magnetic stimulation has been shown to alter local blood flow of the brain, excite the corticospinal tract and muscle, and induce motor function recovery. We established a rat model of acute spinal cord inj...Repetitive magnetic stimulation has been shown to alter local blood flow of the brain, excite the corticospinal tract and muscle, and induce motor function recovery. We established a rat model of acute spinal cord injury using the modified Allen＇s method. After 4 hours of injury, rat models received repetitive magnetic stimulation, with a stimulus intensity of 35% maximum output intensity, 5-Hz frequency, 5 seconds for each sequence, and an interval of 2 minutes. This was repeated for a total of 10 sequences, once a day, 5 days in a week, for 2 consecutive weeks. After repetitive magnetic stimulation, the number of apoptotic cells decreased, matrix metalloproteinase 9/2 gene and protein expression decreased, nestin expression increased, somatosensory and motor-evoked potentials recovered, and motor function recovered in the injured spinal cord. These findings confirm that repetitive magnetic stimulation of the spinal cord improved the microenvironment of neural regeneration, reduced neuronal apoptosis, and induced neuroprotective and repair effects on the injured spinal cord.展开更多
Schwann cell transplantation and hyperbaric oxygen therapy each promote recovery from spinal cord injury, but it remains unclear whether their combination improves therapeutic results more than monotherapy. To investi...Schwann cell transplantation and hyperbaric oxygen therapy each promote recovery from spinal cord injury, but it remains unclear whether their combination improves therapeutic results more than monotherapy. To investigate this, we used Schwann cell transplantation via the tail vein, hyperbaric oxygen therapy, or their combination, in rat models of spinal cord contusion injury. The combined treatment was more effective in improving hindlimb motor function than either treatment alone; injured spinal tissue showed a greater number of neurite-like structures in the injured spinal tissue, somatosensory and motor evoked potential latencies were notably shorter, and their amplitudes greater, after combination therapy than after monotherapy. These findings indicate that Schwann cell transplantation combined with hyperbaric oxygen therapy is more effective than either treatment alone in promoting the recovery of spinal cord in rats after injury.展开更多
The protective effects of erythropoietin on spinal Here, the eukaryotic expression plasmid pcDNA3.1 cord injury have not been well described. human erythropoietin was transfected into rat neural stem cells cultured in...The protective effects of erythropoietin on spinal Here, the eukaryotic expression plasmid pcDNA3.1 cord injury have not been well described. human erythropoietin was transfected into rat neural stem cells cultured in vitro. A rat model of spinal cord injury was established using a free falling object. In the human erythropoietin-neural stem cells group, transfected neural stem cells were injected into the rat subarachnoid cavity, while the neural stem cells group was inject- ed with non-transfected neural stem cells. Dulbecco＇s modified Eagle＇s medium/F12 medium was injected into the rats in the spinal cord injury group as a control. At 1-4 weeks post injury, the motor function in the rat lower limbs was best in the human erythropoietin-neural stem ceils group, followed by the neural stem cells group, and lastly the spinal cord injury group. At 72 hours, compared with the spinal cord injury group, the apoptotic index and Caspase-3 gene and protein expressions were apparently decreased, and the bd-2 gene and protein expressions were noticeably increased, in the tissues surrounding the injured region in the human erythro- poietin-neural stem cells group. At 4 weeks, the somatosensory evoked potential latencies were cavities were clearly smaller and the motor and remarkably shorter in the human erythropoi- etin-neural stem cells group and neural stem cells group than those in the spinal cord injury group. These differences were particularly obvious in the human erythropoietin-neural stem cells group. More CM-Dil-positive cells and horseradish peroxidase-positive nerve fibers and larger amplitude motor and somatosensory evoked potentials were found in the human erythro- poietin-neural stem cells group and neural stem cells group than in the spinal cord injury group. Again, these differences were particularly obvious in the human erythropoietin-neural stem cells group. These data indicate that transplantation of erythropoietin gene-modified neural stem cells into the subarachnoid cavity to help repair spinal cord injury and promote the recovery of spinal cord function better than neural stem cell transplantation alone. These findings may lead to significant improvements in the clinical treatment of spinal cord injuries.展开更多
Transfection of the human telomerase reverse transcriptase（h TERT）gene has been shown to increase cell proliferation and enhance tissue repair.In the present study,h TERT was transfected into rat Schwann cells.A rat...Transfection of the human telomerase reverse transcriptase（h TERT）gene has been shown to increase cell proliferation and enhance tissue repair.In the present study,h TERT was transfected into rat Schwann cells.A rat model of acute spinal cord injury was established by the modified free-falling method.Retrovirus PLXSN was injected at the site of spinal cord injury as a vector to mediate h TERT gene-transfected Schwann cells（1×10^（10）/L;10μL）or Schwann cells（1×10^（10）/L;10μL）without h TERT gene transfection.Between 1 and 4 weeks after model establishment,motor function of the lower limb improved in the h TERT-transfected group compared with the group with non-transfected Schwann cells.Terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling and reverse transcription-polymerase chain reaction results revealed that the number of apoptotic cells,and gene expression of aquaporin 4/9 and matrix metalloproteinase 9/2decreased at the site of injury in both groups;however,the effect improved in the h TERT-transfected group compared with the Schwann cells without h TERT transfection group.Hematoxylin and eosin staining,PKH26 fluorescent labeling,and electrophysiological testing demonstrated that compared with the non-transfected group,spinal cord cavity and motor and sensory evoked potential latencies were reduced,while the number of PKH26-positive cells and the motor and sensory evoked potential amplitude increased at the site of injury in the h TERT-transfected group.These findings suggest that transplantation of h TERT gene-transfected Schwann cells repairs the structure and function of the injured spinal cord.展开更多
Edaravone has been shown to delay neuronal apoptosis, thereby improving nerve function and the microenvironment after spinal cord injury. Edaravone can provide a favorable environment for theAa：eatment of spinal cord...Edaravone has been shown to delay neuronal apoptosis, thereby improving nerve function and the microenvironment after spinal cord injury. Edaravone can provide a favorable environment for theAa：eatment of spinal cord injury using Schwann cell transplantation. This study used rat models of complete spinal cord transection at T9. Six hours later, Schwann cells were transplanted in the head and tail ends of the injury site. Simultaneously, edaravone was injected through the caudal vein. Eight weeks later, the PKH-26-1abeled Schwann cells had survived and migrated to the center of the spinal cord injury region in rats after combined treatment with edaravone and Schwann cells. Moreover, the number of PKH-26-1abeled Schwann cells in the rat spinal cord was more than that in rats undergoing Schwann cell transplantation alone or rats without any treatment. Horseradish peroxidase retrograde tracing revealed that the number of horserad- ish peroxidase-positive nerve fibers was greater in rats treated with edaravone combined with Schwann cells than in rats with Schwann cell transplantation alone. The results demonstrated that lower extremity motor function and neurophysiological function were better in rats treated with edaravone and Schwann cells than in rats with Schwann cell transplantation only. These data confirmed that Schwann cell transplantation combined with edaravone injection promoted the regeneration of nerve fibers of rats with spinal cord injury and improved neurological function.展开更多
Topiramate（TPM） is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in s...Topiramate（TPM） is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in spinal cord injury has not been studied extensively. Thus, we evaluated effects of TPM on secondary cellular injury mechanisms in an experimental rat model of traumatic spinal cord injury（SCI）. After rat models of thoracic contusive SCI were established by free weight-drop method, TPM（40 mg/kg） was given at 12-hour intervals for four times orally. Post TPM treatment, malondialdehyde and protein carbonyl levels were significantly reduced and reduced glutathione levels were increased, while immunoreactivity for endothelial nitric oxide synthase, inducible nitric oxide synthase, and apoptotic peptidase activating factor 1 was diminished in SCI rats. In addition, TPM treatment improved the functional recovery of SCI rats. This study suggests that administration of TPM exerts neuroprotective effects on SCI.展开更多
Electroacupuncture is beneficial for the recovery of spinal cord injury, but the underlying mechanism is unclear. The Rho/Rho-associated kinase（ROCK） signaling pathway regulates the actin cytoskeleton by controlling...Electroacupuncture is beneficial for the recovery of spinal cord injury, but the underlying mechanism is unclear. The Rho/Rho-associated kinase（ROCK） signaling pathway regulates the actin cytoskeleton by controlling the adhesive and migratory behaviors of cells that could inhibit neurite regrowth after neural injury and consequently hinder the recovery from spinal cord injury. Therefore, we hypothesized electroacupuncture could affect the Rho/ROCK signaling pathway to promote the recovery of spinal cord injury. In our experiments, the spinal cord injury in adult Sprague-Dawley rats was caused by an impact device. Those rats were subjected to electroacupuncture at Yaoyangguan（GV3）, Dazhui（GV14）, Zusanli（ST36） and Ciliao（BL32） and/or monosialoganglioside treatment. Behavioral scores revealed that the hindlimb motor functions improved with those treatments. Real-time quantitative polymerase chain reaction, fluorescence in situ hybridization and western blot assay showed that electroacupuncture suppressed the m RNA and protein expression of Rho-A and Rho-associated kinase Ⅱ（ROCKⅡ） of injured spinal cord. Although monosialoganglioside promoted the recovery of hindlimb motor function, monosialoganglioside did not affect the expression of Rho-A and ROCKⅡ. However, electroacupuncture combined with monosialoganglioside did not further improve the motor function or suppress the expression of Rho-A and ROCKⅡ. Our data suggested that the electroacupuncture could specifically inhibit the activation of the Rho/ROCK signaling pathway thus partially contributing to the repair of injured spinal cord. Monosialoganglioside could promote the motor function but did not suppress expression of Rho A and ROCKⅡ. There was no synergistic effect of electroacupuncture combined with monosialoganglioside.展开更多
Because of their strong proliferative capacity and multi-potency, placenta-derived mesenchymal stem cells have gained interest as a cell source in the field of nerve damage repair. In the present study, human placenta...Because of their strong proliferative capacity and multi-potency, placenta-derived mesenchymal stem cells have gained interest as a cell source in the field of nerve damage repair. In the present study, human placenta-derived mesenchymal stem ceils were induced to differentiate into neural stem cells, which were then transplanted into the spinal cord after local spinal cord injury in rats. The motor functional recovery and pathological changes in the injured spinal cord were observed for 3 successive weeks. The results showed that human placenta-derived mesenchymal stem cells can differentiate into neuron-like cells and that induced neural stem cells contribute to the restoration of injured spinal cord without causing transplant rejection. Thus, these cells promote the recovery of motor and sensory functions in a rat model of spinal cord injury. Therefore, human placenta-derived mesenchymal stem cells may be useful as seed cells during the repair of spinal cord injury.展开更多
The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could...The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an in-creased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deifcits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.展开更多
A spinal cord hemisection injury model was established in rats. Treatment with IN-1 and/or neurotrophin-3 was found to regulate the expression of growth-associated protein 43, nerve growth factor, and basic fibroblast...A spinal cord hemisection injury model was established in rats. Treatment with IN-1 and/or neurotrophin-3 was found to regulate the expression of growth-associated protein 43, nerve growth factor, and basic fibroblast growth factor genes in the injured spinal cord tissues; transcript levels were first increased and then decreased. Expression levels reached a peak at days 7 （growth-associated protein 43） or 14 （nerve growth factor and basic fibroblast growth factor） following spinal cord injury. Combined treatment with neurotrophin-3 and IN-1 achieved the most apparent effect on the expression and recovery of motor function. These findings confirm that combined therapy with neurotrophin-3 and IN-1 can increase expression of growth factors in the injured spinal cord tissues and promote the axonal reaeneration.展开更多
BACKGROUND： Numerous studies have shown that tumor necrosis factor α （TNF-α） is closely correlated with spinal cord injury （SCI）, but the mechanisms of TNF-α and therapeutic treatments for SCI are still poorly...BACKGROUND： Numerous studies have shown that tumor necrosis factor α （TNF-α） is closely correlated with spinal cord injury （SCI）, but the mechanisms of TNF-α and therapeutic treatments for SCI are still poorly understood. OBJECTIVE： To determine the role of TNF-α in the pathogenesis of SCI. DESIGN, TIME AND SETTING： An in vivo experiment based on genetically engineered animals was performed at the Medical University of South Carolina, Charleston, South Carolina, USA, between June 2007 and October 2008. MATERIALS： TNF-α transgenic rats （Xenogen Biosciences in Cranbury, New Jersey, USA） were utilized in this study. METHODS： TNF-α transgenic （tg） and wild-type （WT） rats underwent a complete single-level laminectomy at the 10^th thoracic vertebra （T10）. MAIN OUTCOME MEASURES： Motor function of rat hindlimb was assessed using the Basso, Beattie, and Bresnahan hindlimb locomotor rating scale. Histological evaluation of spinal cord tissue loss was conducted. Immunohistochemistry for astrocytes, microglia/macrophages, and TNF receptors （TNFRs） was performed on spinal cord tissue sections. TNF-α mRNA expression was detected by real-time polymerase chain reaction. The concentrations of nerve growth factor （NGF） and brain-derived neurotrophic factor （BDNF） in the supernatant were determined using an enzyme-linked immunosorbent assay kit for rat NGF or BDNF, respectively. The rats were injected subcutaneously with etanercept to verify that TNF-α was the direct effect of the modulation of behavioral and neurodegenerative outcomes in the TNF-α tg rats. RESULTS： TNF-α tg rats showed higher expression of TNF-α mRNA in the spinal cord prior to SCI. TNF-α tg rats showed worse motor deficits than WT rats in the acute period （〈 3 days） after SCI （P 〈 0.01）, while in the chronic period, TNF-α tg rats exhibited persistent elevated baseline levels of TNF-α mRNA and improved recovery in motor function and tissue healing compared to WT rats （P 〈 0.01 ）. Following SCI, the number of microglia/macrophages in TNF-α tg rat was always greater than in WT rat （P 〈 0.01）. There were no significant differences in NGF and BDNF levels in the supernatant of spinal cord homogenates. TNFR1 expression was significantly greater in the TNF-α tg rats compared to the WT rats （P 〈 0.01）. However, TNFR2 expression did not reveal a significant increase in the TNF-α tg rats compared to the WT rats. Finally, treatment with etanercept reduced injury acutely, but exacerbated the injury chronically. CONCLUSION： Overexpression of TNF-α is deleterious in the acute phase, but beneficial in the chronic phase in the response to SCI. The role of TNF-α post-injury may depend on TNF-α expression in the spinal cord and its differential binding to TNFRI. Our observations may have clinical relevance that antagonists or inhibitors of TNF-α could be administered within the early time window post-injury, and appropriate amounts of TNF-α could be administered during the chronic stage, in order to improve the final neurological recovery in patients with SCI.展开更多
Spinal cord ischemia associated with trauma and surgical procedures including thoraco-abdominal aortic aneurysm repair and thoracic endovascular aortic repair results in devastating clinical deficits in patients. Beca...Spinal cord ischemia associated with trauma and surgical procedures including thoraco-abdominal aortic aneurysm repair and thoracic endovascular aortic repair results in devastating clinical deficits in patients. Because spinal cord ischemia is inadequately treated, we studied the effects of [4-((1 E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1 H-pyrazoyl-3-yl) vinyl)-2-methoxy-phenol)](CNB-001), a novel curcumin-based compound, in a rabbit SCI model. CNB-001 is known to inhibit human 5-lipoxygenase and 15-lipoxygenase and reduce the ischemia-induced inflammatory response. Moreover, CNB-001 can reduce the level of oxidative stress markers and potentiate brain-derived neurotrophic factor and brain-derived neurotrophic factor receptor signaling. The Tarlov scale and quantal analysis technique results revealed that CNB-001 administered as an intravenous dose(bolus) 30 minutes prior to spinal cord ischemia improved the behaviors of female New Zealand White rabbits. The improvements were similar to those produced by the uncompetitive N-methyl-D-aspartate receptor antagonist memantine. At 48 hours after aortic occlusion, there was a 42.7% increase(P < 0.05) in tolerated ischemia duration(n = 14) for rabbits treated with CNB-001(n = 16), and a 72.3% increase for rabbits treated with the positive control memantine(P < 0.05)(n = 23) compared to vehicle-treated ischemic rabbits(n = 22). CNB-001 is a potential important novel treatment for spinal cord ischemia induced by aortic occlusion. All experiments were approved by the CSMC Institutional Animal Care and Use Committee(IACUC #4311) on November 1,2012.展开更多
Spinal cord injury （SCI） is a major cause of disability. A serious consequence of SCI is the loss or partialloss of motor control. A number of therapies are currently being developed for restoring motor function in ...Spinal cord injury （SCI） is a major cause of disability. A serious consequence of SCI is the loss or partialloss of motor control. A number of therapies are currently being developed for restoring motor function in SCI patients. However, such approaches generally require intact neural motor systems for driving limb movements. There is evidence that SCI can generate such conditions in the brain,展开更多
基金supported by the National Natural Science Foundation of China,No.81371663,61534003the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions of China,No.PPZY2015B135
文摘Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience.The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology.In this study,the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology.A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn.Based on the individual experimental parameters and normalized coordinates of the motor function sites,the motor function sites that control a certain muscle were calculated.Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension,hip flexion,ankle plantarflexion,and ankle dorsiflexion movements were successfully achieved.The results show that the map of the spinal cord motor function sites was valid.This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury.
文摘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.
基金supported by the National Natural Science Foundation of China,No.81704096,81603635,81873317(to MY,JY,XJC)Shanghai Science and Technology Commission-Key Project of Traditional Chinese Medicine,No.16401970100(to YJW)+4 种基金the Shanghai Traditional Chinese Medicine Medical Center of Chronic Disease of China,No.2017ZZ01010(to YJW)the National Thirteenth Five-Year Science and Technology Major Special Project for New Drug Innovation and Development of China,No.2017ZX09304001(to YJW)the Program for Innovative Research Team of Ministry of Science and Technology of China,No.2015RA4002(to YJW)the “Innovation Team” Development Projects of China,No.IRT1270(to YJW)the Three Years Action to Accelerate the Development of Traditional Chinese Medicine Plan of China,No.ZY(2018-2020)-CCCX-3003(to YJW)
文摘Objective:Studies have shown that docosahexaenoic acid(DHA)has a beneficial effect in the treatment of spinal cord injury.A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spinal cord injury model,and the relationship between the recovery of motor function after spinal cord injury and the time and method of administration and the dose of DHA.Data source:Published studies on the effect of DHA on spinal cord injury animal models from seven databases were searched from their inception to January 2019,including PubMed,MEDLINE,EMBASE,the China National Knowledge Infrastructure,Wanfang,VIP,and SinoMed databases.The search terms included“spinal cord injury”“docosahexaenoic acid”,and“rats”.Data selection:Studies that evaluated the influence of DHA in rat models of spinal cord injury for locomotor functional recovery were included.The intervention group included any form of DHA treatment and the control group included treatment with normal saline,vehicle solution or no treatment.The Systematic Review Centre for Laboratory animal Experimentation’s risk of bias assessment tool was used for the quality assessment of the included studies.Literature inclusion,quality evaluation and data extraction were performed by two researchers.Meta-analysis was then conducted on all studies that met the inclusion criteria.Statistical analysis was performed on the data using RevMan 5.1.2.software.Outcome measures:The primary outcome measure was the score on the Basso,Beattie,and Bresnahan scale.Secondary outcome measures were the sloping plate test,balance beam test,stair test and grid exploration test.Results:A total of 12 related studies were included,3 of which were of higher quality and the remaining 9 were of lower quality.The highest mean Basso,Beattie,and Bresnahan scale score occurred at 42 days after DHA treatment in spinal cord injury rats.At 21 days after treatment,the mean difference in Basso,Beattie,Bresnahan scores between the DHA group and the control group was the most significant(pooled MD=4.14;95%CI=3.58–4.70;P<0.00001).In the subgroup analysis,improvement in the Basso,Beattie,and Bresnahan scale score was more significant in rats administered DHA intravenously(pooled MD=2.74;95%CI=1.41–4.07;P<0.0001)and subcutaneously(pooled MD=2.99;95%CI=2.29–3.69;P<0.00001)than in the groups administered DHA orally(pooled MD=3.04;95%CI=–1.01 to 7.09;P=0.14).Intravenous injection of DHA at 250 nmol/kg(pooled MD=2.94;95%CI=2.47–3.41;P<0.00001]and 1000 nmol/kg[pooled MD=3.60;95%CI=2.66–4.54;P<0.00001)significantly improved the Basso,Beattie,and Bresnahan scale score in rats and promoted the recovery of motor function.Conclusion:DHA can promote motor functional recovery after spinal cord injury in rats.The administration of DHA by intravenous or subcutaneous injection is more effective than oral administration of DHA.Intravenous injection of DHA at doses of 250 nmol/kg or 1000 nmol/kg is beneficial.Because of the small number and the low quality of the included studies,more high-quality research is needed in future to substantiate the results.
文摘The repair effects of bone marrow mesenchymal stem cell transplantation on nervous system damage are not satisfactory. Propofol has been shown to protect against spinal cord injury. Therefore, this study sought to explore the therapeutic effects of their combination on spinal cord injury. Rat models of spinal cord injury were established using the weight drop method. Rats were subjected to bone marrow mesenchymal stem cell transplantationvia tail vein injection and/or propofol injectionvia tail vein using an infusion pump. Four weeks after cell transplan-tation and/or propofol treatment, the cavity within the spinal cord was reduced. The numbers of PKH-26-positive cells and horseradish peroxidase-positive nerve ifbers apparently increased in the spinal cord. Latencies of somatosensory evoked potentials and motor evoked potentials in the hindlimb were noticeably shortened, amplitude was increased and hindlimb motor function was obviously improved. Moreover, the combined effects were better than cell transplantation or propofol injection alone. The above data suggest that the combination of propofol injection and bone marrow mesenchymal stem cell transplantation can effectively improve hindlimb electro-physiological function, promote the recovery of motor funtion, and play a neuroprotective role in spinal cord injury in rats.
基金supported by a grant from the Science and Technology Development Plan of Jilin Province of China,No.2011084
文摘Senegenin has been shown to inhibit neuronal apoptosis,thereby exerting a neuroprotective effect.In the present study,we established a rat model of spinal cord contusion injury using the modified Allen＇s method.Three hours after injury,senegenin（30 mg/g） was injected into the tail vein for 3 consecutive days.Senegenin reduced the size of syringomyelic cavities,and it substantially reduced the number of apoptotic cells in the spinal cord.At the site of injury,Bax and Caspase-3 m RNA and protein levels were decreased by senegenin,while Bcl-2 m RNA and protein levels were increased.Nerve fiber density was increased in the spinal cord proximal to the brain,and hindlimb motor function and electrophysiological properties of rat hindlimb were improved.Taken together,our results suggest that senegenin exerts a neuroprotective effect by suppressing neuronal apoptosis at the site of spinal cord injury.
基金financially supported by grants from the Science and Technology Development Project of Jilin Province in China,No.20110492
文摘Clinical studies have shown that hyperbaric oxygen therapy improves motor function in patients with spinal cord injury. In the present study, we explored the mechanisms associated with the recovery of neurological function after hyperbaric oxygen therapy in a rat model of spinal cord injury. We established an acute spinal cord injury model using a modification of the free-falling object method, and treated the animals with oxygen at 0.2 MPa for 45 minutes, 4 hours after injury. The treatment was administered four times per day, for 3 days. Compared with model rats that did not receive the treatment, rats exposed to hyperbaric oxygen had fewer apoptotic cells in spinal cord tissue, lower expression levels of aquaporin 4/9 mRNA and protein, and more NF-200 positive nerve fibers. Furthermore, they had smaller spinal cord cavities, rapid recovery of somatosensory and motor evoked potentials, and notably better recovery of hindlimb motor function than model rats. Our findings indicate that hyperbaric oxygen therapy reduces apoptosis, downregulates aquaporin 4/9 mRNA and protein expression in injured spinal cord tissue, improves the local microenvironment for nerve regeneration, and protects and repairs the spinal cord after injury.
文摘Repetitive magnetic stimulation has been shown to alter local blood flow of the brain, excite the corticospinal tract and muscle, and induce motor function recovery. We established a rat model of acute spinal cord injury using the modified Allen＇s method. After 4 hours of injury, rat models received repetitive magnetic stimulation, with a stimulus intensity of 35% maximum output intensity, 5-Hz frequency, 5 seconds for each sequence, and an interval of 2 minutes. This was repeated for a total of 10 sequences, once a day, 5 days in a week, for 2 consecutive weeks. After repetitive magnetic stimulation, the number of apoptotic cells decreased, matrix metalloproteinase 9/2 gene and protein expression decreased, nestin expression increased, somatosensory and motor-evoked potentials recovered, and motor function recovered in the injured spinal cord. These findings confirm that repetitive magnetic stimulation of the spinal cord improved the microenvironment of neural regeneration, reduced neuronal apoptosis, and induced neuroprotective and repair effects on the injured spinal cord.
文摘Schwann cell transplantation and hyperbaric oxygen therapy each promote recovery from spinal cord injury, but it remains unclear whether their combination improves therapeutic results more than monotherapy. To investigate this, we used Schwann cell transplantation via the tail vein, hyperbaric oxygen therapy, or their combination, in rat models of spinal cord contusion injury. The combined treatment was more effective in improving hindlimb motor function than either treatment alone; injured spinal tissue showed a greater number of neurite-like structures in the injured spinal tissue, somatosensory and motor evoked potential latencies were notably shorter, and their amplitudes greater, after combination therapy than after monotherapy. These findings indicate that Schwann cell transplantation combined with hyperbaric oxygen therapy is more effective than either treatment alone in promoting the recovery of spinal cord in rats after injury.
基金supported by the Science and Technology Development Program of Jilin Province of China,No.2011084
文摘The protective effects of erythropoietin on spinal Here, the eukaryotic expression plasmid pcDNA3.1 cord injury have not been well described. human erythropoietin was transfected into rat neural stem cells cultured in vitro. A rat model of spinal cord injury was established using a free falling object. In the human erythropoietin-neural stem cells group, transfected neural stem cells were injected into the rat subarachnoid cavity, while the neural stem cells group was inject- ed with non-transfected neural stem cells. Dulbecco＇s modified Eagle＇s medium/F12 medium was injected into the rats in the spinal cord injury group as a control. At 1-4 weeks post injury, the motor function in the rat lower limbs was best in the human erythropoietin-neural stem ceils group, followed by the neural stem cells group, and lastly the spinal cord injury group. At 72 hours, compared with the spinal cord injury group, the apoptotic index and Caspase-3 gene and protein expressions were apparently decreased, and the bd-2 gene and protein expressions were noticeably increased, in the tissues surrounding the injured region in the human erythro- poietin-neural stem cells group. At 4 weeks, the somatosensory evoked potential latencies were cavities were clearly smaller and the motor and remarkably shorter in the human erythropoi- etin-neural stem cells group and neural stem cells group than those in the spinal cord injury group. These differences were particularly obvious in the human erythropoietin-neural stem cells group. More CM-Dil-positive cells and horseradish peroxidase-positive nerve fibers and larger amplitude motor and somatosensory evoked potentials were found in the human erythro- poietin-neural stem cells group and neural stem cells group than in the spinal cord injury group. Again, these differences were particularly obvious in the human erythropoietin-neural stem cells group. These data indicate that transplantation of erythropoietin gene-modified neural stem cells into the subarachnoid cavity to help repair spinal cord injury and promote the recovery of spinal cord function better than neural stem cell transplantation alone. These findings may lead to significant improvements in the clinical treatment of spinal cord injuries.
基金supported by a grant from the Science and Technology Development Plan Program of Jilin Province of China,No.2011084
文摘Transfection of the human telomerase reverse transcriptase（h TERT）gene has been shown to increase cell proliferation and enhance tissue repair.In the present study,h TERT was transfected into rat Schwann cells.A rat model of acute spinal cord injury was established by the modified free-falling method.Retrovirus PLXSN was injected at the site of spinal cord injury as a vector to mediate h TERT gene-transfected Schwann cells（1×10^（10）/L;10μL）or Schwann cells（1×10^（10）/L;10μL）without h TERT gene transfection.Between 1 and 4 weeks after model establishment,motor function of the lower limb improved in the h TERT-transfected group compared with the group with non-transfected Schwann cells.Terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling and reverse transcription-polymerase chain reaction results revealed that the number of apoptotic cells,and gene expression of aquaporin 4/9 and matrix metalloproteinase 9/2decreased at the site of injury in both groups;however,the effect improved in the h TERT-transfected group compared with the Schwann cells without h TERT transfection group.Hematoxylin and eosin staining,PKH26 fluorescent labeling,and electrophysiological testing demonstrated that compared with the non-transfected group,spinal cord cavity and motor and sensory evoked potential latencies were reduced,while the number of PKH26-positive cells and the motor and sensory evoked potential amplitude increased at the site of injury in the h TERT-transfected group.These findings suggest that transplantation of h TERT gene-transfected Schwann cells repairs the structure and function of the injured spinal cord.
文摘Edaravone has been shown to delay neuronal apoptosis, thereby improving nerve function and the microenvironment after spinal cord injury. Edaravone can provide a favorable environment for theAa：eatment of spinal cord injury using Schwann cell transplantation. This study used rat models of complete spinal cord transection at T9. Six hours later, Schwann cells were transplanted in the head and tail ends of the injury site. Simultaneously, edaravone was injected through the caudal vein. Eight weeks later, the PKH-26-1abeled Schwann cells had survived and migrated to the center of the spinal cord injury region in rats after combined treatment with edaravone and Schwann cells. Moreover, the number of PKH-26-1abeled Schwann cells in the rat spinal cord was more than that in rats undergoing Schwann cell transplantation alone or rats without any treatment. Horseradish peroxidase retrograde tracing revealed that the number of horserad- ish peroxidase-positive nerve fibers was greater in rats treated with edaravone combined with Schwann cells than in rats with Schwann cell transplantation alone. The results demonstrated that lower extremity motor function and neurophysiological function were better in rats treated with edaravone and Schwann cells than in rats with Schwann cell transplantation only. These data confirmed that Schwann cell transplantation combined with edaravone injection promoted the regeneration of nerve fibers of rats with spinal cord injury and improved neurological function.
基金partly supported by Turkish Neurosurgical Society
文摘Topiramate（TPM） is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in spinal cord injury has not been studied extensively. Thus, we evaluated effects of TPM on secondary cellular injury mechanisms in an experimental rat model of traumatic spinal cord injury（SCI）. After rat models of thoracic contusive SCI were established by free weight-drop method, TPM（40 mg/kg） was given at 12-hour intervals for four times orally. Post TPM treatment, malondialdehyde and protein carbonyl levels were significantly reduced and reduced glutathione levels were increased, while immunoreactivity for endothelial nitric oxide synthase, inducible nitric oxide synthase, and apoptotic peptidase activating factor 1 was diminished in SCI rats. In addition, TPM treatment improved the functional recovery of SCI rats. This study suggests that administration of TPM exerts neuroprotective effects on SCI.
基金supported by the National Natural Science Foundation of China,No.81360562
文摘Electroacupuncture is beneficial for the recovery of spinal cord injury, but the underlying mechanism is unclear. The Rho/Rho-associated kinase（ROCK） signaling pathway regulates the actin cytoskeleton by controlling the adhesive and migratory behaviors of cells that could inhibit neurite regrowth after neural injury and consequently hinder the recovery from spinal cord injury. Therefore, we hypothesized electroacupuncture could affect the Rho/ROCK signaling pathway to promote the recovery of spinal cord injury. In our experiments, the spinal cord injury in adult Sprague-Dawley rats was caused by an impact device. Those rats were subjected to electroacupuncture at Yaoyangguan（GV3）, Dazhui（GV14）, Zusanli（ST36） and Ciliao（BL32） and/or monosialoganglioside treatment. Behavioral scores revealed that the hindlimb motor functions improved with those treatments. Real-time quantitative polymerase chain reaction, fluorescence in situ hybridization and western blot assay showed that electroacupuncture suppressed the m RNA and protein expression of Rho-A and Rho-associated kinase Ⅱ（ROCKⅡ） of injured spinal cord. Although monosialoganglioside promoted the recovery of hindlimb motor function, monosialoganglioside did not affect the expression of Rho-A and ROCKⅡ. However, electroacupuncture combined with monosialoganglioside did not further improve the motor function or suppress the expression of Rho-A and ROCKⅡ. Our data suggested that the electroacupuncture could specifically inhibit the activation of the Rho/ROCK signaling pathway thus partially contributing to the repair of injured spinal cord. Monosialoganglioside could promote the motor function but did not suppress expression of Rho A and ROCKⅡ. There was no synergistic effect of electroacupuncture combined with monosialoganglioside.
基金supported by a grant from the Scientific Research Program of Liaoning Provincial Science and Technology Ministry in China,No.2012225014
文摘Because of their strong proliferative capacity and multi-potency, placenta-derived mesenchymal stem cells have gained interest as a cell source in the field of nerve damage repair. In the present study, human placenta-derived mesenchymal stem ceils were induced to differentiate into neural stem cells, which were then transplanted into the spinal cord after local spinal cord injury in rats. The motor functional recovery and pathological changes in the injured spinal cord were observed for 3 successive weeks. The results showed that human placenta-derived mesenchymal stem cells can differentiate into neuron-like cells and that induced neural stem cells contribute to the restoration of injured spinal cord without causing transplant rejection. Thus, these cells promote the recovery of motor and sensory functions in a rat model of spinal cord injury. Therefore, human placenta-derived mesenchymal stem cells may be useful as seed cells during the repair of spinal cord injury.
基金supported by Proj.PRIN prot.2007AF3XH4_005,"Fondazione Cassa di Risparmio di Roma",and"Ministero della Salute"Grant No.RF-FGB-2005-150198
文摘The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an in-creased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deifcits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.
基金a project by Hunan Provincial Health Department, No. B2005-076
文摘A spinal cord hemisection injury model was established in rats. Treatment with IN-1 and/or neurotrophin-3 was found to regulate the expression of growth-associated protein 43, nerve growth factor, and basic fibroblast growth factor genes in the injured spinal cord tissues; transcript levels were first increased and then decreased. Expression levels reached a peak at days 7 （growth-associated protein 43） or 14 （nerve growth factor and basic fibroblast growth factor） following spinal cord injury. Combined treatment with neurotrophin-3 and IN-1 achieved the most apparent effect on the expression and recovery of motor function. These findings confirm that combined therapy with neurotrophin-3 and IN-1 can increase expression of growth factors in the injured spinal cord tissues and promote the axonal reaeneration.
基金the ES016774-01A1VA Merit Award and National Science Foundation EPSCoR grant, No. EPS-0132573+1 种基金EPS-0447660 (MSK)NS050452-05 (JJH)
文摘BACKGROUND： Numerous studies have shown that tumor necrosis factor α （TNF-α） is closely correlated with spinal cord injury （SCI）, but the mechanisms of TNF-α and therapeutic treatments for SCI are still poorly understood. OBJECTIVE： To determine the role of TNF-α in the pathogenesis of SCI. DESIGN, TIME AND SETTING： An in vivo experiment based on genetically engineered animals was performed at the Medical University of South Carolina, Charleston, South Carolina, USA, between June 2007 and October 2008. MATERIALS： TNF-α transgenic rats （Xenogen Biosciences in Cranbury, New Jersey, USA） were utilized in this study. METHODS： TNF-α transgenic （tg） and wild-type （WT） rats underwent a complete single-level laminectomy at the 10^th thoracic vertebra （T10）. MAIN OUTCOME MEASURES： Motor function of rat hindlimb was assessed using the Basso, Beattie, and Bresnahan hindlimb locomotor rating scale. Histological evaluation of spinal cord tissue loss was conducted. Immunohistochemistry for astrocytes, microglia/macrophages, and TNF receptors （TNFRs） was performed on spinal cord tissue sections. TNF-α mRNA expression was detected by real-time polymerase chain reaction. The concentrations of nerve growth factor （NGF） and brain-derived neurotrophic factor （BDNF） in the supernatant were determined using an enzyme-linked immunosorbent assay kit for rat NGF or BDNF, respectively. The rats were injected subcutaneously with etanercept to verify that TNF-α was the direct effect of the modulation of behavioral and neurodegenerative outcomes in the TNF-α tg rats. RESULTS： TNF-α tg rats showed higher expression of TNF-α mRNA in the spinal cord prior to SCI. TNF-α tg rats showed worse motor deficits than WT rats in the acute period （〈 3 days） after SCI （P 〈 0.01）, while in the chronic period, TNF-α tg rats exhibited persistent elevated baseline levels of TNF-α mRNA and improved recovery in motor function and tissue healing compared to WT rats （P 〈 0.01 ）. Following SCI, the number of microglia/macrophages in TNF-α tg rat was always greater than in WT rat （P 〈 0.01）. There were no significant differences in NGF and BDNF levels in the supernatant of spinal cord homogenates. TNFR1 expression was significantly greater in the TNF-α tg rats compared to the WT rats （P 〈 0.01）. However, TNFR2 expression did not reveal a significant increase in the TNF-α tg rats compared to the WT rats. Finally, treatment with etanercept reduced injury acutely, but exacerbated the injury chronically. CONCLUSION： Overexpression of TNF-α is deleterious in the acute phase, but beneficial in the chronic phase in the response to SCI. The role of TNF-α post-injury may depend on TNF-α expression in the spinal cord and its differential binding to TNFRI. Our observations may have clinical relevance that antagonists or inhibitors of TNF-α could be administered within the early time window post-injury, and appropriate amounts of TNF-α could be administered during the chronic stage, in order to improve the final neurological recovery in patients with SCI.
文摘Spinal cord ischemia associated with trauma and surgical procedures including thoraco-abdominal aortic aneurysm repair and thoracic endovascular aortic repair results in devastating clinical deficits in patients. Because spinal cord ischemia is inadequately treated, we studied the effects of [4-((1 E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1 H-pyrazoyl-3-yl) vinyl)-2-methoxy-phenol)](CNB-001), a novel curcumin-based compound, in a rabbit SCI model. CNB-001 is known to inhibit human 5-lipoxygenase and 15-lipoxygenase and reduce the ischemia-induced inflammatory response. Moreover, CNB-001 can reduce the level of oxidative stress markers and potentiate brain-derived neurotrophic factor and brain-derived neurotrophic factor receptor signaling. The Tarlov scale and quantal analysis technique results revealed that CNB-001 administered as an intravenous dose(bolus) 30 minutes prior to spinal cord ischemia improved the behaviors of female New Zealand White rabbits. The improvements were similar to those produced by the uncompetitive N-methyl-D-aspartate receptor antagonist memantine. At 48 hours after aortic occlusion, there was a 42.7% increase(P < 0.05) in tolerated ischemia duration(n = 14) for rabbits treated with CNB-001(n = 16), and a 72.3% increase for rabbits treated with the positive control memantine(P < 0.05)(n = 23) compared to vehicle-treated ischemic rabbits(n = 22). CNB-001 is a potential important novel treatment for spinal cord ischemia induced by aortic occlusion. All experiments were approved by the CSMC Institutional Animal Care and Use Committee(IACUC #4311) on November 1,2012.
文摘Spinal cord injury （SCI） is a major cause of disability. A serious consequence of SCI is the loss or partialloss of motor control. A number of therapies are currently being developed for restoring motor function in SCI patients. However, such approaches generally require intact neural motor systems for driving limb movements. There is evidence that SCI can generate such conditions in the brain,
