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2.
Neural Regen Res ; 14(3): 532-541, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30539824

RESUMO

Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows: (1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group. (2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group. (3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury. (4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group. (5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2 (ACSF2) and iron-responsive element-binding protein 2 (IREB2) were up-regulated in the Deferoxamine group. (6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.

3.
Cell Physiol Biochem ; 45(6): 2506-2515, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29554650

RESUMO

BACKGROUND/AIMS: Low back pain has become one of the most common musculoskeletal diseases in the world. Studies have shown that intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the mechanisms underlying IDD remain largely unknown. Research over the past decade has suggested critical roles for microRNAs (miRNAs) in natural growth and disease progression. However, it remains poorly understood whether circular RNAs participate in IDD. METHODS: Clinical IDD samples were collected from 20 patients who underwent discectomy. Weighted gene co-expression network analysis was used to identify the co-expression miRNA network modules (highly co-expressed clusters of miRNAs) that were associated with IDD grade. RESULTS: miR-3150a-3p was the most significantly up-regulated miRNA in module "Blue." Notably, aggrecan (ACAN) was identified as a direct target gene of miR-3150a-3p and ACAN expression was regulated by miR-3150a-3p. Overexpression of miR-3150a-3p decreased ACAN expression in nucleus pulposus cells, whereas inhibition of miR-3150a-3p increased ACAN expression. In addition, ACAN expression was negatively correlated with IDD grade. CONCLUSION: Our study suggests that the reduction of ACAN expression induced by the upregulation of miR-3150a-3p might participate in the development of IDD.


Assuntos
Agrecanas/genética , Degeneração do Disco Intervertebral/genética , MicroRNAs/metabolismo , Adulto , Regulação para Baixo , Feminino , Humanos , Degeneração do Disco Intervertebral/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Regulação para Cima
4.
CNS Neurosci Ther ; 24(5): 429-438, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29352519

RESUMO

AIM: Spinal cord injury (SCI) leads to severe neural damage for which there is currently no effective treatment. Exploration of the neuroprotective effect among clinically approved drugs will speed up clinical translation of SCI. Nafamostat mesilate (NM) as a synthetic serine protease inhibitor has been used clinically in pancreatitis treatments. However, its effectiveness in SCI is unknown. The aim of this study was to confirm the efficacy of NM in ameliorating SCI. METHODS: Intraperitoneal administration of NM was performed on a contusion SCI model in Wistar rat. Hematoxylin and eosin staining (H&E staining) and Luxol fast blue (LFB) staining were used to observe the histological lesions. Apoptosis was examined by TUNEL staining, Annexin V-FITC/PI, caspase-3, and Bcl-2. Cytokines and neurotrophins were tested by Western blot. Locomotion recovery assessed by hindlimb BBB score and the inclined plane test. RESULTS: Nafamostat mesilate treatment significantly improved locomotion recovery as assessed by hindlimb BBB scores and the inclined plane test. H&E staining and LFB staining showed a significant increase in spared tissue in both gray matter and white matter. NM decreased the expression of the proinflammatory cytokines TNF-α and IL-6. In addition, apoptosis was also significantly decreased, as shown by TUNEL staining and Annexin V-FITC/PI and by Western blotting for caspase-3 and Bcl-2 expression. Due to the mechanism of action of NM as a serine protease inhibitor, the drug decreased thrombin expression in the damaged spinal cord. Furthermore, NM increased the expression of neurotrophins (NT-3, BDNF, and NGF). CONCLUSIONS: Upon NM treatment, the functional and histological outcomes were improved, and microenvironment upon SCI was modulated. As a clinically approved drug, NM holds promise for clinical use after spinal cord injury.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Guanidinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Modelos Animais de Doenças , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Distribuição Aleatória , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
5.
Neural Regen Res ; 12(6): 959-968, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28761430

RESUMO

Deferoxamine, a clinically safe drug used for treating iron overload, also repairs spinal cord injury although the mechanism for this action remains unknown. Here, we determined whether deferoxamine was therapeutic in a rat model of spinal cord injury and explored potential mechanisms for this effect. Spinal cord injury was induced by impacting the spinal cord at the thoracic T10 vertebra level. One group of injured rats received deferoxamine, a second injured group received saline, and a third group was sham operated. Both 2 days and 2 weeks after spinal cord injury, total iron ion levels and protein expression levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß and the pro-apoptotic protein caspase-3 in the spinal cords of the injured deferoxamine-treated rats were significantly lower than those in the injured saline-treated group. The percentage of the area positive for glial fibrillary acidic protein immunoreactivity and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were also significantly decreased both 2 days and 2 weeks post injury, while the number of NeuN-positive cells and the percentage of the area positive for the oligodendrocyte marker CNPase were increased in the injured deferoxamine-treated rats. At 14-56 days post injury, hind limb motor function in the deferoxamine-treated rats was superior to that in the saline-treated rats. These results suggest that deferoxamine decreases total iron ion, tumor necrosis factor-α, interleukin-1ß, and caspase-3 expression levels after spinal cord injury and inhibits apoptosis and glial scar formation to promote motor function recovery.

6.
Int J Mol Med ; 39(6): 1381-1392, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440471

RESUMO

Long non-coding RNAs (lncRNAs) are widely accepted as key players in various biological processes. However, the roles of lncRNA in peripheral nerve regeneration remain completely unknown. Thus, in this study, we performed microarray analysis to measure lncRNA expression in the distal segment of the sciatic nerve at 0, 3, 7 and 14 days following injury. We identified 5,354 lncRNAs that were differentially expressed: 3,788 lncRNAs were differentially expressed between days 0 and 3; 3,314 lncRNAs were differentially expressed between days 0 and 7; and 2,400 lncRNAs were differentially expressed between days 0 and 14. The results of RT-qPCR of two dysregulated lncRNAs were consistent with those of microarray analysis. Bioinformatics approaches, including lncRNA classification, gene ontology (GO) analysis and target prediction, were utilized to investigate the functions of these dysregulated lncRNAs in peripheral nerve damage. Importantly, we predicted that several lncRNA-mRNA pairs may participate in biological processes related to peripheral nerve injury. RT-qPCR was performed for the preliminary verification of three lncRNA­mRNA pairs. The overexpression of NONMMUG014387 promoted the proliferation of mouse Schwann cells. Thus, the findings of our study may enhance our knowledge of the role of lncRNAs in nerve injury.


Assuntos
Perfilação da Expressão Gênica , Traumatismos dos Nervos Periféricos/genética , RNA Longo não Codificante/genética , Animais , Proliferação de Células , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Genômica , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo
7.
Muscle Nerve ; 55(3): 373-383, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27313142

RESUMO

INTRODUCTION: The purpose of this study was to provide a comprehensive understanding of gene expression during Wallerian degeneration and axon regeneration after peripheral nerve injury. METHODS: A microarray was used to detect gene expression in the distal nerve 0, 3, 7, and 14 days after sciatic nerve crush. Bioinformatic analysis was used to predict function of the differentially expressed mRNAs. Microarray results and the key pathways were validated by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Differentially expressed mRNAs at different time-points (3, 7, and 14 days) after injury were identified and compared with a control group (0 day). Nine general trends of changes in gene expression were identified. Key signal pathways and 9 biological processes closely associated with nerve regeneration were identified and verified. CONCLUSIONS: Differentially expressed genes and biological processes and pathways associated with axonal regeneration may elucidate the molecular-biological mechanisms underlying peripheral nerve regeneration. Muscle Nerve 55: 373-383, 2017.


Assuntos
Regulação da Expressão Gênica/fisiologia , Expressão Gênica/fisiologia , Regeneração Nervosa/fisiologia , Neuropatia Ciática/fisiopatologia , Transdução de Sinais/genética , Animais , Biologia Computacional , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , RNA Mensageiro/metabolismo , Fatores de Tempo
8.
Brain Res ; 1586: 46-63, 2014 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-25152470

RESUMO

After spinal cord injury (SCI), the rapidly upregulated chondroitin sulfate proteoglycans (CSPGs), the prominent chemical constituents and main repulsive factors of the glial scar, play an important role in the extremely limited ability to regenerate in adult mammals. Although many methods to overcome the inhibition have been tested, no successful method with clinical feasibility has been devised to date. It was recently discovered that receptor protein tyrosine phosphatase sigma (RPTPσ) is a functional receptor for CSPGs-mediated inhibition. In view of the potential clinical application of RNA interference (RNAi), here we investigated whether silencing RPTPσ via lentivirus-mediated RNA interference can promote axon regeneration and functional recovery after SCI. Neurites of primary rat cerebral cortical neurons with depleted RPTPσ exhibited a significant enhancement in elongation and crossing ability when they encountered CSPGs in vitro. A contusion model of spinal cord injury in Wistar rats (the New York University (NYU) impactor) was used for in vivo experiments. Local injection of lentivirus encoding RPTPσ shRNA at the lesion site promoted axon regeneration and synapse formation, but did not affect the scar formation. Meanwhile, in vivo functional recovery (motor and sensory) was also enhanced after RPTPσ depletion. Therefore, strategies directed at silencing RPTPσ by RNAi may prove to be a beneficial, efficient and valuable approach for the treatment of SCI.


Assuntos
Córtex Cerebral/patologia , Neuritos/fisiologia , Neurônios/patologia , RNA Interferente Pequeno/fisiologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal , Animais , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Regeneração Nervosa/fisiologia , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Fatores de Tempo , Transfecção , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
9.
Virusdisease ; 25(3): 294-301, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25674596

RESUMO

RNA interference (RNAi) has been successfully used as a promising method to inhibit the replication of different viruses, including human immunodeficiency virus (HIV). Gene mutation is a hurdle for the anti-HIV by RNAi. Although prone to mutation, some genes are conserved and limited in functionally important regions. The gag gene is conserved in different subtypes and plays an important role in the assembly of HIV viral particle. Here, we identified subtypes and conserved sequences within forty-four gag genes from the epidemic strains among men who have sex with men. Three subtypes of gag gene, including CRF01_AE (47.7 %), CRF07_BC (40.9 %) and B (11.4 %) were analyzed by online blast. We designed five small hairpin RNAs (shRNAs) based on the conserved sequences. The gag-EGFP fusion transcript reporter system was used to select the most efficient shRNA. Among the five candidate shRNAs, gag-shRNA-3 represented a broad-spectrum inhibition against all chosen targets. This broad-spectrum shRNA diminished the titer of subtypes B and C of HIV-1 for a hundred orders of magnitude. The gag-shRNA-3 described here is a potential therapeutic agent in the HIV-1 gene therapy.

10.
Cell Transplant ; 21 Suppl 1: S39-47, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22507679

RESUMO

Schwann cells (SCs) are the main glial cells of the peripheral nervous system, which can promote neural regeneration. Grafting of autologous SCs is one of the well-established and commonly performed procedures for peripheral nerve repair. With the aim to improve the clinical condition of patients with spinal cord injury (SCI), a program of grafting autologous activated Schwann cells (AASCs), as well as a series of appropriate neurorehabilitation programs, was employed to achieve the best therapeutic effects. We selected six patients who had a history of SCI before transplantation. At first, AASCs were obtained by prior ligation of sural nerve and subsequently isolated, cultured, and purified in vitro. Then the patients accepted an operation of laminectomy and cell transplantation, and no severe adverse event was observed in any of these patients. Motor and sensitive improvements were evaluated by means of American Spinal Injury Association (ASIA) grading and Functional Independence Measure (FIM); bladder and urethral function were determined by clinical and urodynamic examination; somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) were used to further confirm the functional recovery following transplantation. The patients were followed up for more than 5 years. All of the patients showed some signs of improvement in autonomic, motor, and sensory function. So we concluded that AASC transplantation might be feasible, safe, and effective to promote neurorestoration of SCI patients.


Assuntos
Regeneração Nervosa/fisiologia , Células de Schwann/transplante , Traumatismos da Medula Espinal/cirurgia , Adolescente , Adulto , Técnicas de Cultura de Células , Criança , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Células de Schwann/citologia
11.
Virol Sin ; 26(6): 403-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22160940

RESUMO

The ubiquitin-like modifier bISG15 is an antiviral protein found in fetal bovine lung (FBL) cells. Bovine Herpesvirus 1(BHV-1), which is a viral pathogen of cattle, can infect FBL cells and induce cytopathic effects. Real-time PCR assays showed that BHV-1's infection could repress the basal or inducible transcription of bISG15 in FBL cells. It demonstrates that this repression effect depends on BHV-1 viral infection and new protein synthesis. Our previous work showed that bIRF-3 was the key factor in the stimulation of bISG15 in FBL cells, so the effect of BHV-1 viral protein on bIRF-3 activating the promoter of bISG15 was confirmed. The luciferase assay showed the BHV-1 viral protein bICP0 inhibited the activation of bISG15 promoter stimulated by bIRF-3. Taken together, our work suggested that BHV-1 had some molecular mechanism to resist the cellular bISG15's antiviral functions.


Assuntos
Doenças dos Bovinos/genética , Regulação para Baixo , Infecções por Herpesviridae/veterinária , Herpesvirus Bovino 1/metabolismo , Transativadores/metabolismo , Transcrição Genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/genética , Animais , Bovinos , Doenças dos Bovinos/metabolismo , Doenças dos Bovinos/virologia , Linhagem Celular , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/virologia , Herpesvirus Bovino 1/genética , Humanos , Pulmão/metabolismo , Pulmão/virologia , Transativadores/genética , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética
12.
Virol Sin ; 26(3): 147-55, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21667335

RESUMO

Perinatal transmission of Human immunodeficiency virus (HIV), also called mother-to-child transmission (MTCT), accounts for 90% of infections in infants worldwide and occurs in 30%-45% of children born to untreated HIV-1 infected mothers. Among HIV-1 infected mothers, some viruses are transmitted from mothers to their infants while others are not. The relationship between virologic properties and the pathogenesis caused by HIV-1 remains unclear. Previous studies have demonstrated that one obvious source of selective pressure in the perinatal transmission of HIV-1 is maternal neutralizing antibodies. Recent studies have shown that viruses which are successfully transmitted to the child have growth advantages over those not transmitted, when those two viruses are grown together. Furthermore, the higher fitness is determined by the gp120 protein of the virus envelope. This suggests that the selective transmission of viruses with higher fitness occurred exclusively, regardless of transmission routes. There are many factors contributing to the selective transmission and HIV replicative fitness is an important one that should not be neglected. This review summarizes current knowledge of the role of HIV replicative fitness in HIV MTCT transmission and the determinants of viral fitness upon MTCT.


Assuntos
Infecções por HIV/transmissão , HIV-1/fisiologia , Transmissão Vertical de Doença Infecciosa , Complicações Infecciosas na Gravidez/virologia , Replicação Viral , Animais , Feminino , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Gravidez
13.
J Drug Target ; 18(6): 420-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19954414

RESUMO

The blood-spinal cord barrier (BSCB) prevents many macromolecular agents from passing through to reach sites of injury in the spinal cord. This study evaluated the ability of a novel multifunctional liposome modified with polyethylene glycol (PEG) and transactivating-transduction protein (TAT) containing an iron core to cross the BSCB using a rat model of spinal cord injury. Rats were examined daily for a period of three days after spinal cord injury and injection of either the multifunctional modified liposome or control formulations using a 3.0 T magnetic resonance imaging spectrometer. A low signal was observed in the T2-weighted images. Prussian blue staining and flame atomic absorption spectrophotometry revealed that significantly more iron accumulated around the lesion site in the experimental group than the control groups (P < 0.05). The findings from this study suggest that this multifunctional liposome carrier can cross the BSCB to accumulate around the lesion site.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Produtos do Gene tat/química , Fragmentos de Peptídeos/química , Polietilenoglicóis/química , Traumatismos da Medula Espinal/sangue , Medula Espinal/irrigação sanguínea , Animais , Quitosana/administração & dosagem , Quitosana/análogos & derivados , Quitosana/química , Quitosana/farmacocinética , Colesterol/administração & dosagem , Colesterol/química , Colesterol/farmacocinética , Modelos Animais de Doenças , Produtos do Gene tat/administração & dosagem , Produtos do Gene tat/farmacocinética , Ferro/química , Lipossomos , Imagem por Ressonância Magnética , Magnetismo , Microscopia Eletrônica de Transmissão , Nanopartículas , Tamanho da Partícula , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacocinética , Peptídeos/administração & dosagem , Peptídeos/química , Peptídeos/farmacocinética , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Ratos , Espectrofotometria Atômica , Medula Espinal/metabolismo , Medula Espinal/ultraestrutura , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Propriedades de Superfície
14.
Orthop Surg ; 1(2): 153-63, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-22009833

RESUMO

OBJECTIVE: Transplantation of fetal spinal cord cells (FSCC) can promote regeneration of injured spinal cord, while Schwann cells (SC) and some growth factors have a similar effect. However, the synergistic effects and optimal combination of these modalities have not yet been evaluated. In the current study, the efficiency of cell therapy of FSCC and/or SC, with/without growth factors (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF]) was examined, with the aim of establishing an optimized protocol for spinal cord injury. METHODS: One hundred and twenty adult rats were randomly divided into six groups with 20 rats in each group. One week after the thoracic spinal cord injury model had been created, the rats were treated with different therapeutic modalities: Dulbecco's modified Eagles medium (DMEM) in Group I, FSCC in Group II, FSCC plus SC in Group III, FSCC plus SC over-expressing NGF in Group IV, FSCC plus SC over-expressing BDNF in Group V, and FSCC plus SC over-expressing both NGF and BDNF in Group VI. Subsequently, the rats were subjected to behavioral tests once a week after injury, while histology, immunohistochemistry and electron microscopy were performed at one and three month post-operation. RESULTS: Both SC and FSCC promoted regeneration of spinal cord injury when used separately, while a combination of the two types of cell resulted in better recovery than either alone. Both growth factors (NGF and BDNF) enhanced the outcomes of cell therapy, while synergistic effects meant that a combination of each individual component (group VI) achieved the best results according to locomotion scale, histology and immunoreactivity in the injured cords. CONCLUSION: SC, NGF and BDNF can enhance the outcome of FSCC therapy, while the combination of FSC with SC, NGF and BDNF is possibly the optimal protocol for clinical treatment of acute spinal cord injury.


Assuntos
Transplante de Células/métodos , Terapia Genética/métodos , Regeneração Nervosa , Traumatismos da Medula Espinal/terapia , Medula Espinal/transplante , Animais , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Imuno-Histoquímica , Microscopia Eletrônica , Fatores de Crescimento Neural/biossíntese , Ratos , Ratos Wistar , Medula Espinal/ultraestrutura , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Vértebras Torácicas
15.
Brain Res ; 1256: 149-61, 2009 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-19103176

RESUMO

Basic research in spinal cord injury (SCI) has made great strides in recent years, and some new insights and strategies have been applied in promoting effective axonal regrowth and sprouting. However, a relatively safe and efficient transplantation technique remains undetermined. This study, therefore, was aimed to address a question of how to graft Schwann cells to achieve the best possible therapeutic effects. To clarify the issue, the rats were subjected to spinal cord injury at T10. Autologous activated Schwann cells (AASCs) were obtained by prior ligation of saphenous nerve and subsequently isolated and purified in vitro and then grafted into spinal cord-injured rats via three different routes (group I: intravenous, group II: intrathecal and group III: intraspinal cord). Neurologic function was serially evaluated by Basso, Beattie, Bresnahan locomotor rating scale and footprint analysis. We also evaluated the migration of the transplanted cells at 2 weeks after transplantation. Using biotinylated dextran amine (BDA) anterograde tracing, we demonstrated that more regenerative axons of corticospinal tract (CST) surrounding the injured cavity in group III than those in the other two groups, and we also confirmed it further by quantitative analysis. The microenvironment surrounding the injured spinal cord has been improved to the greatest extent in group III, as determined by immunohistological staining. Relatively complete myelin sheaths and more neurofilaments in axons were found in groups II and III than those in group I under electron microscopy. The results showed that intraspinal cord injection of AASCs promoted recovery of hindlimb locomotor function of injured rats more efficiently than the other grafting routes. In addition, intact myelin sheaths and sufficient neurofilaments in axons were not adequate for full functional recovery after SCI, suggesting that reestablishment of normal synaptic connection is indispensable. The findings in this study strongly suggest that transplantation of AASCs directly into the spinal cord may be one of the promising candidates for potential scaffold for injured spinal cord, and such strategy of transplantation of AASCs could be hopeful to treat patients with SCI.


Assuntos
Axônios/fisiologia , Regeneração Nervosa , Recuperação de Função Fisiológica , Células de Schwann/transplante , Traumatismos da Medula Espinal/terapia , Análise de Variância , Animais , Axônios/ultraestrutura , Células Cultivadas , Feminino , Imuno-Histoquímica , Microscopia Eletrônica , Atividade Motora , Bainha de Mielina/fisiologia , Bainha de Mielina/ultraestrutura , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/fisiopatologia
16.
Neurotox Res ; 7(1-2): 169-77, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15639807

RESUMO

Fetal spinal cord cells, Schwann cells and neurotrophins all have the capacity to promote repair of injured spinal cord in animal models. To explore the possibility of using these approaches to treat clinical patients, we have examined whether a combination of these protocols produces functional and anatomical improvement. The spinal cords of adult rats (n=16) were injured with a modified New York University (NYU) device (10 gram.5cm). One week after injury, the injured cords were injected with Dulbecco-modified Eagles Medium (DMEM, control group), or fetal spinal cord cell suspension (FSCS) plus nerve growth factor (NGF) gene-modified Schwann cells (SC) and brain-derived neurotrophic factor (BDNF) gene-modified SC (treatment group). The rats were subjected to BBB (Basso, Beattie, Bresnahan, Exp. Neurol. 139:244, 1996) behavioral tests. Anterograde tracing of corticospinal tract was performed before sacrifice 3 months after the treatment. The results showed that the combination treatment elicited a robust growth of corticospinal axons within and beyond the injury site. A dramatic functional recovery in the treatment group was observed compared with the control group. We conclude that the combination of FSCS with genetically modified Schwann cells over-expressing NGF and BDNF was an effective protocol for the treatment of severe spinal cord injury.


Assuntos
Transplante de Tecido Fetal/métodos , Células de Schwann/transplante , Traumatismos da Medula Espinal/cirurgia , Medula Espinal/transplante , Animais , Transplante de Células/métodos , Células Cultivadas , Feminino , Engenharia Genética/métodos , Humanos , Masculino , Camundongos , Gravidez , Ratos , Ratos Sprague-Dawley , Células de Schwann/fisiologia , Nervo Isquiático/transplante , Traumatismos da Medula Espinal/genética , Transfecção/métodos
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