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1.
Life Sci ; 245: 117351, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31981629

RESUMO

AIMS: To study the specific therapeutic effect of zinc on spinal cord injury (SCI) and its specific protective mechanism. MAIN METHODS: The effects of zinc ions on neuronal cells were examined in a mouse SCI model and in vitro. In vivo, neurological function was assessed by Basso Mouse Scaleat (BMS) at 1, 3, 5, 7, 10, 14, 21, and 28 days after spinal cord injury. The number of neurons and histomorphology were observed by nissl staining and hematoxylin-eosin staining (HE). The chromatin and mitochondrial structure of neurons were detected by transmission electron microscopy (TEM). The expression of nuclear factor erythroid 2 related factor 2 (Nrf2)-related antioxidant protein and NLRP3 inflammation-related protein were detected in vivo and in vitro by western blot (WB) and immunofluorescence (IF), respectively. KEY FINDINGS: Zinc treatment promoted motor function recovery on days 3, 5, 7, 14, 21 and 28 after SCI. In addition, zinc reduces the mitochondrial void rate in spinal neuronal cells and promotes neuronal recovery. At the same time, zinc reduced the levels of reactive oxygen species (ROS) and malondialdehyde in spinal cord tissue after SCI, while increasing superoxide dismutase activity and glutathione peroxidase production. Zinc treatment resulted in up-regulation of Nrf2/Ho-1 levels and down-regulation of nlrp3 inflammation-associated protein expression in vitro and in vivo. SIGNIFICANCE: Zinc has a protective effect on spinal cord injury by inhibiting oxidative damage and nlrp3 inflammation. Potential mechanisms may include activation of the Nrf 2/Ho-1 pathway to inhibit nlrp3 inflammation following spinal cord injury. Zinc has the potential to treat SCI.


Assuntos
Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Zinco/uso terapêutico , Animais , Western Blotting , Modelos Animais de Doenças , Feminino , Imunofluorescência , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Zinco/farmacologia
2.
J Photochem Photobiol B ; 203: 111741, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31901721

RESUMO

Spinal cord injury (SCI) is a distressing injury and an irretrievable dramatic event that can debilitate victims for lifespan. Recovery and treatment of SCI is critical challenges for medicine, to overcome the hurdles stem cells and hydrogel scaffolds implantation is a boon for SCI recovery. In this regard, we reported the synthesis of Gold nanoparticles (Au NPs) loaded Agarose/Poly (N-isopropylacrylamide) (PNIPAM) as promising materials for SCI treatment. Herein, Au NPs was synthesized by well-established citrate reduction method and the prepared materials were characterised by UV-visible spectroscopy (UV-vis), Transmission electron microscopy (TEM), Fourier- transform infrared spectroscopy (FT-IR), Scanning electron microscopy (SEM), and EDAX analysis. The microscopic images showed an elliptical or ovoid porous structure nature of hydrogel, and successful and homogenous loading of photo plasmonic nanoparticles into the hydrogel structure. The in vitro cell viability and inflammation analyses data exhibited that prepared hydrogels have no toxic to the cells and displayed high anti-regenerative ability with bone marrow Mesenchymal stem cells (MSCs) and macrophages cells. The in vivo analysis study demonstrated that the treated materials with encapsulated MSCs have greater nerve tissue regeneration efficacy which was confirmed by the results of BBB scores. The hind limb locomotion of treated model animals was totally vanished after post-operational surgery. It's established that implanted nano-hydrogel materials combined with MSCs have quicker recovery of motor function after post-operative surgery, when compared to the other implanted animal groups.


Assuntos
Materiais Biocompatíveis/química , Hidrogéis/química , Transplante de Células-Tronco Mesenquimais , Nanopartículas Metálicas/química , Traumatismos da Medula Espinal/terapia , Bexiga Urinária/fisiopatologia , Resinas Acrílicas/química , Animais , Células da Medula Óssea/citologia , Ouro/química , Membro Posterior/fisiologia , Locomoção , Células-Tronco Mesenquimais/química , Células-Tronco Mesenquimais/citologia , Tecido Nervoso/fisiologia , Regeneração , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/patologia , Tecidos Suporte/química
3.
Medicine (Baltimore) ; 98(52): e18509, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876739

RESUMO

To evaluate progression of skin atrophy during 8 years of complete Conus-Cauda Syndrome and its recovery after 2 years of surface Functional Electrical Stimulation a cohort study was organized and implemented.Functional assessments, tissue biopsies, and follow-up were performed at the Wilhelminenspital, Vienna, Austria; skin histology and immunohistochemistry at the University of Padova, Italy on 13 spinal cord injury persons suffering up to 10 years of complete conus/cauda syndrome. Skin biopsies (n. 52) of both legs were analyzed before and after 2 years of home-based Functional Electrical Stimulation delivered by large anatomically shaped surface electrodes placed on the skin of the anterior thigh. Using quantitative histology we analyzed: 1. Epidermis atrophy by thickness and by area; 2. Skin flattening by computing papillae per mm and Interdigitation Index of dermal-epidermal junctions; 3. Presence of Langerhans cells.Linear regression analyses show that epidermal atrophy and flattening worsen with increasing years post- spinal cord injury and that 2 years of skin electrostimulation by large anatomically shaped electrodes reverses skin changes (pre-functional Electrical Stimulation vs post-functional Electrical Stimulation: thickness 39%, P < .0001; area 41%, P < .0001; papillae n/mm 35%, P < 0.0014; Interdigitation index 11%, P < 0.018), producing a significant recovery to almost normal levels of epidermis thickness and of dermal papillae, with minor changes of Langerhans cells, despite 2 additional years of complete Conus-Cauda Syndrome.In complete Conus-Cauda Syndrome patients, the well documented beneficial effects of 2 years of surface h-b Functional Electrical Stimulation on strength, bulk, and muscle fiber size of thigh muscles are extended to skin, suggesting that electrical stimulation by anatomically shaped electrodes fixed to the skin is also clinically relevant to counteract atrophy and flattening of the stimulated skin. Mechanisms, pros and cons are discussed.


Assuntos
Terapia por Estimulação Elétrica/métodos , Epiderme/patologia , Dermatopatias/terapia , Traumatismos da Medula Espinal/complicações , Medula Espinal , Adulto , Atrofia , Biópsia , Humanos , Pessoa de Meia-Idade , Pele/patologia , Dermatopatias/etiologia , Dermatopatias/patologia , Traumatismos da Medula Espinal/patologia , Síndrome , Coxa da Perna , Adulto Jovem
4.
Nat Rev Neurol ; 15(12): 718-731, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31673093

RESUMO

Pathophysiological changes in the spinal cord white and grey matter resulting from injury can be observed with MRI techniques. These techniques provide sensitive markers of macrostructural and microstructural tissue integrity, which correlate with histological findings. Spinal cord MRI findings in traumatic spinal cord injury (tSCI) and nontraumatic spinal cord injury - the most common form of which is degenerative cervical myelopathy (DCM) - have provided important insights into the pathophysiological processes taking place not just at the focal injury site but also rostral and caudal to the spinal injury. Although tSCI and DCM have different aetiologies, they show similar degrees of spinal cord pathology remote from the injury site, suggesting the involvement of similar secondary degenerative mechanisms. Advanced quantitative MRI protocols that are sensitive to spinal cord pathology have the potential to improve diagnosis and, more importantly, predict outcomes in patients with tSCI or nontraumatic spinal cord injury. This Review describes the insights into tSCI and DCM that have been revealed by neuroimaging and outlines current activities and future directions for the field.


Assuntos
Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Traumatismos da Medula Espinal/diagnóstico por imagem , Traumatismos da Medula Espinal/patologia , Imagem de Tensor de Difusão/métodos , Humanos
5.
Life Sci ; 237: 116978, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31644893

RESUMO

AIMS: The activation of NLRP3 inflammasome, which initiates an inflammatory cascade and triggers inflammatory death, plays a crucial role in the pathogenesis of spinal cord injury (SCI). Echinacoside (ECH) is a phenylethanoid glycoside possessing prominent anti-inflammatory effects and various neuroprotective properties in the central nervous system, but the effect of ECH on SCI was rarely studied. Therefore, the purpose of this experiment was to look into the therapeutic effects of ECH on SCI and the underlying mechanisms. MAIN METHODS: Basso-Beattie-Bresnahan (BBB) locomotion scale, Nissl staining, and hematoxylin-eosin (HE) staining was employed to examine the therapeutic effects of ECH on SCI. In addition, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) in BV-2 cells stimulated with lipopolysaccharides and adenosine 5'-triphosphate were examined. The expression levels of proteins involving NLRP3 inflammasome-related pathway were measured. KEY FINDINGS: The in vivo experiment indicated that administration of ECH significantly enhanced the BBB scores, reduced the neuron loss, and ameliorated the tissue architecture after SCI. Additionally, ECH dramatically inhibited NLRP3 inflammasome activation in the rat SCI model. In vitro study indicated that ECH significantly reduced ROS level, improved the MMP, blocked activation of NF-κB, and inhibited the NLRP3 inflammasome signaling pathway. The effect of ECH on inhibition of NLRP3 inflammasome signaling pathway was partially governed by suppression of the generation of ROS and activation of NF-κB. SIGNIFICANCE: ECH can accelerate motor function recovery in rats following SCI by inhibiting NLRP3 inflammasome-related signaling pathway, suggesting that ECH may serve as a potential therapeutic agent for treating SCI.


Assuntos
Glicosídeos/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/prevenção & controle , Animais , Inflamação/complicações , Locomoção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/patologia
6.
Nat Commun ; 10(1): 4594, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597914

RESUMO

Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO+-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues.


Assuntos
Linfonodos/fisiologia , Vasos Linfáticos/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Coluna Vertebral/fisiologia , Ducto Torácico/fisiologia , Animais , Processamento de Imagem Assistida por Computador/métodos , Linfonodos/anatomia & histologia , Vasos Linfáticos/anatomia & histologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência , Traumatismos da Medula Espinal/patologia , Coluna Vertebral/anatomia & histologia , Ducto Torácico/anatomia & histologia
7.
Exp Neurol ; 322: 113046, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31472115

RESUMO

Imaging the dynamic interactions between immune cells, glia, neurons and the vasculature in living rodents has revolutionized our understanding of physiological and pathological mechanisms of the CNS. Emerging microscopy and imaging technologies have enabled longitudinal tracking of structural and functional changes in a plethora of different cell types in the brain. The development of novel methods also allowed stable and longitudinal optical access to the spinal cord with minimum tissue perturbation. These important advances facilitated the application of in vivo imaging using two-photon microscopy for studies of the healthy, diseased, or injured spinal cord. Indeed, decoding the interactions between peripheral and resident cells with the spinal cord vasculature has shed new light on neuroimmune and vascular mechanisms regulating the onset and progression of neurological diseases. This review focuses on imaging studies of the interactions between the vasculature and peripheral immune cells or microglia, with emphasis on their contribution to neuroinflammation. We also discuss in vivo imaging studies highlighting the importance of neurovascular changes following spinal cord injury. Real-time imaging of blood-brain barrier (BBB) permeability and other vascular changes, perivascular glial responses, and immune cell entry has revealed unanticipated cellular mechanisms and novel molecular pathways that can be targeted to protect the injured or diseased CNS. Imaging the cell-cell interactions between the vasculature, immune cells, and neurons as they occur in real time, is a powerful tool both for testing the efficacy of existing therapeutic approaches, and for identifying new targets for limiting damage or enhancing the potential for repair of the affected spinal cord tissue.


Assuntos
Neuroimagem/métodos , Medula Espinal , Animais , Barreira Hematoencefálica/patologia , Medula Espinal/imunologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia
8.
Neurology ; 93(16): e1550-e1560, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31541012

RESUMO

OBJECTIVE: To investigate the spatiotemporal evolution and predictive properties of intramedullary damage and midsagittal tissue bridges at the epicenter of a thoracic spinal cord injury (SCI) using MRI. METHODS: We retrospectively assessed midsagittal T2-weighted scans from 25 patients with thoracic SCI (14 traumatic, 11 ischemic) at 1 month post-SCI. In 12 patients with SCI, linear mixed-effects models on serial MRI explored temporal trajectories of quantifiable lesion markers (area, length, and width) and tissue bridges. Using partial correlation analysis, we assessed associations between structural lesion characteristics at 1 month post-SCI and recovery at 1 year postinjury, adjusting for baseline clinical status, age, and sex. RESULTS: Lesion area decreased by 5.68 mm2 (p = 0.005), lesion length by 2.14 mm (p = 0.004), and lesion width by 0.13 mm (p = 0.004) per month. Width of tissue bridges increased by 0.06 mm (p = 0.019) per month, being similar in traumatic and ischemic SCI (p = 0.576). Smaller lesion area, length, width, and wider tissue bridges at 1 month post-SCI predicted better recovery at 1-year follow-up. CONCLUSIONS: Over time, the immediate area of cord damage shrunk while the cystic cavity became demarcated. Adjacent to the cyst, midsagittal tissue bridges became visible. The width of tissue bridges at 1 month post-SCI predicted recovery at 1 year follow-up. Measures of lesion area and tissue bridges early after traumatic and ischemic thoracic SCI therefore allow characterizing the evolution of focal cord damage and are predictive of recovery in thoracic SCI. Thus, lesion extent and tissue bridges hold potential to improve diagnosis and patient stratification in interventional trials.


Assuntos
Medula Cervical/patologia , Isquemia/patologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/patologia , Adulto , Biomarcadores/análise , Medula Cervical/fisiopatologia , Feminino , Humanos , Isquemia/fisiopatologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia
9.
Mol Med Rep ; 20(4): 3011-3018, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432119

RESUMO

Spinal cord injury (SCI) is a specific type of damage to the central nervous system causing temporary or permanent changes in its function. The present aimed to identify the genetic changes in neuroplasticity following SCI in rats. The GSE52763 microarray dataset, which included 15 samples [3 sham (1 week), 4 injury only (1 week), 4 injury only (3 weeks), 4 injury + treadmill (3 weeks)] was downloaded from the Gene Expression Omnibus database. An empirical Bayes linear regression model in limma package was used to identify the differentially expressed genes (DEGs) in injury vs. sham and treadmill vs. non­treadmill comparison groups. Subsequently, time series and enrichment analyses were performed using pheatmap and clusterProfile packages, respectively. Additionally, protein­protein interaction (PPI) and transcription factor (TF)­microRNA (miRNA)­target regulatory networks were constructed using Cytoscape software. In total, 159 and 105 DEGs were identified in injury vs. sham groups and treadmill vs. non­treadmill groups, respectively. There were 40 genes in cluster 1 that presented increased expression levels in the injury (1 week/3 weeks) groups compared with the sham group, and decreased expression levels in the injury + treadmill group compared with the injury only groups; conversely, 52 genes in cluster 2 exhibited decreased expression levels in the injury (1 week/3 weeks) groups compared with the sham group, and increased expression levels in the injury + treadmill group compared with the injury only groups. Enrichment analysis indicated that clusters 1 and 2 were associated with immune response and signal transduction, respectively. Furthermore, microtubule associated protein 1B, phosphofurin acidic cluster sorting protein 2 and adenosylhomocysteinase­like 1 exhibited the highest degrees in the regulatory network, and were regulated by miRNAs including miR­34A, miR­34B, miR­34C and miR­449. These miRNAs and their target genes may serve important roles in neuroplasticity following traumatic SCI in rats. Nevertheless, additional in­depth studies are required to confirm these data.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , MicroRNAs/biossíntese , Proteínas Associadas aos Microtúbulos/biossíntese , Plasticidade Neuronal , Análise de Sequência com Séries de Oligonucleotídeos , Traumatismos da Medula Espinal/metabolismo , Proteínas de Transporte Vesicular/biossíntese , Animais , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Ratos , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/patologia , Proteínas de Transporte Vesicular/genética
10.
Mol Med Rep ; 20(4): 3433-3439, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432160

RESUMO

Icariin is a type of flavonoid derived from the Chinese herbal plant Epimedium sagittatum Maxim. Mounting evidence has confirmed the beneficial effects of icariin in neurological diseases, including spinal cord injury (SCI). The aim of the present study was to investigate the neuroprotective effects of icariin in SCI and the precise underlying mechanism. The weight­drop injury technique was applied to construct an SCI model in Sprague­Dawley rats. Icariin (35 µmol/kg) was administered orally once daily for 7 consecutive days to examine its neuroprotective effects. The Basso, Beattie and Bresnahan scoring system was used for neurobehavioral evaluation. The water content of the injured spinal cord was measured via the dry­wet weight method. Biochemical indices were examined by colorimetric assay using commercially available kits. Western blot analysis was used to detect protein expression. Icariin significantly accelerated the recovery of the locomotor function of SCI rats and decreased spinal cord water content. Icariin also attenuated SCI­induced pro­apoptotic protein expression and activity, while it increased anti­apoptotic protein levels. In addition, icariin alleviated oxidative stress in SCI rats and decreased the levels of inflammatory molecules, including interleukin (IL)­1ß, IL­6, tumor necrosis factor­α, nitric oxide, nuclear factor­κB and inducible nitric oxide synthase, and increased the expression of anti­inflammatory proteins, including NADPH­quinone oxidoreductase­1, heme oxygenase­1 and nuclear factor erythroid 2­related factor 2 in the injured spinal cord. Therefore, icariin treatment accelerated locomotor function recovery in SCI, and its protective effects may be mediated via its antioxidant, anti­inflammatory and anti­apoptotic bioactivity.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
11.
Nat Commun ; 10(1): 3879, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462640

RESUMO

Traumatic spinal cord injury results in severe and irreversible loss of function. The injury triggers a complex cascade of inflammatory and pathological processes, culminating in formation of a scar. While traditionally referred to as a glial scar, the spinal injury scar in fact comprises multiple cellular and extracellular components. This multidimensional nature should be considered when aiming to understand the role of scarring in limiting tissue repair and recovery. In this Review we discuss recent advances in understanding the composition and phenotypic characteristics of the spinal injury scar, the oversimplification of defining the scar in binary terms as good or bad, and the development of therapeutic approaches to target scar components to enable improved functional outcome after spinal cord injury.


Assuntos
Cicatriz/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Astrócitos/patologia , Humanos , Inflamação , Neuroglia/patologia , Traumatismos da Medula Espinal/patologia , Regeneração da Medula Espinal , Cicatrização
12.
Clinics (Sao Paulo) ; 74: e674, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31433044

RESUMO

OBJECTIVE: To evaluate the effects of interleukin-6 (IL-6) and erythropoietin (EPO) in experimental acute spinal cord injury (SCI) in rats. METHODS: Using standardized equipment, namely, a New York University (NYU) Impactor, a SCI was produced in 50 Wistar rats using a 10-g weight drop from a 12.5-mm height. The rats were divided into the following 5 groups of 10 animals each: "Group EPO", treated with erythropoietin only; "Group EPO + IL-6", treated with both substances; "Group IL-6", receiving IL-6 administration only; "Group Placebo", receiving a placebo solution; and "Group Sham", submitted to an incomplete procedure (only laminectomy, without SCI). All drugs and the placebo solution were administered intraperitoneally for three weeks. The animals were followed up for 42 days. Functional motor recovery was monitored by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35 and 42. Motor-evoked potential tests were performed on the 42nd day. Histological analysis was performed after euthanasia. RESULTS: The group receiving EPO exhibited superior functional motor results on the BBB scale. IL-6 administration alone was not superior to the placebo treatment, and the IL-6 combination with EPO yielded worse results than did EPO alone. CONCLUSIONS: Using EPO after acute SCI in rats yielded benefits in functional recovery. The combination of EPO and IL-6 showed benefits, but with inferior results compared to those of isolated EPO; moreover, isolated use of IL-6 resulted in no benefit.


Assuntos
Eritropoetina/uso terapêutico , Potencial Evocado Motor/efeitos dos fármacos , Interleucina-6/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Modelos Animais de Doenças , Eritropoetina/farmacologia , Interleucina-6/farmacologia , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia
13.
J Orthop Surg Res ; 14(1): 199, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266512

RESUMO

BACKGROUND: We focused on the therapeutic effects of the stable gastric pentadecapeptide BPC 157 in spinal cord injury using a rat model. BPC 157, of which the LD1 has not been achieved, has been implemented as an anti-ulcer peptide in inflammatory bowel disease trials and recently in a multiple sclerosis trial. In animals, BPC 157 has an anti-inflammatory effect and therapeutic effects in functional recovery and the rescue of somatosensory neurons in the sciatic nerve after transection, upon brain injury after concussive trauma, and in severe encephalopathies. Additionally, BPC 157 affects various molecular pathways. METHODS: Therefore, BPC 157 therapy was administered by a one-time intraperitoneal injection (BPC 157 (200 or 2 µg/kg) or 0.9% NaCl (5 ml/kg)) 10 min after injury. The injury procedure involved laminectomy (level L2-L3) and a 60-s compression (neurosurgical piston (60-66 g) of the exposed dural sac of the sacrocaudal spinal cord). Assessments were performed at 1, 4, 7, 15, 30, 90, 180, and 360 days after injury. RESULTS: All of the injured rats that received BPC 157 exhibited consistent clinical improvement, increasingly better motor function of the tail, no autotomy, and resolved spasticity by day 15. BPC 157 application largely counteracted changes at the microscopic level, including the formation of vacuoles and the loss of axons in the white matter, the formation of edema and the loss of motoneurons in the gray matter, and a decreased number of large myelinated axons in the rat caudal nerve from day 7. EMG recordings showed a markedly lower motor unit potential in the tail muscle. CONCLUSION: Axonal and neuronal necrosis, demyelination, and cyst formation were counteracted. The functional rescue provided by BPC 157 after spinal cord injury implies that BPC 157 therapy can impact all stages of the secondary injury phase.


Assuntos
Fragmentos de Peptídeos/administração & dosagem , Proteínas/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Eletromiografia/métodos , Humanos , Vértebras Lombares , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/patologia , Cicatrização/fisiologia
14.
J Neuroinflammation ; 16(1): 141, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288834

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a condition with few effective treatment options. The blood-spinal cord barrier consists of pericytes, astrocytes, and endothelial cells, which are collectively termed the neurovascular unit. These cells support spinal cord homeostasis by expressing tight junction proteins. Physical trauma to the spinal cord disrupts the barrier, which leads to neuroinflammation by facilitating immune cell migration to the damaged site in a process involving immune cell adhesion. Immunosuppressive strategies, including methylprednisolone (MPSS), have been investigated to treat SCI. However, despite some success, MPSS has the potential to increase a patient's susceptibility to wound infection and impaired wound healing. Hence, immunomodulation may be a more attractive approach than immunosuppression. Approved for modulating neuroinflammation in certain disorders, including Guillain-Barre syndrome, intravenous administration of human immunoglobulin G (hIgG) has shown promise in the setting of experimental SCI, though the optimal dose and mechanism of action remain undetermined. METHODS: Female adult Wistar rats were subjected to moderate-severe clip compression injury (35 g) at the C7-T1 level and randomized to receive a single intravenous (IV) bolus of hIgG (0.02, 0.2, 0.4, 1, 2 g/kg), MPSS (0.03 g/kg), or control buffer at 15 min post-SCI. At 24 h and 6 weeks post-SCI, molecular, histological, and neurobehavioral effects of hIgG were analyzed. RESULTS: At 24 h post-injury, human immunoglobulin G co-localized with spinal cord pericytes, astrocytes, and vessels. hIgG (2 g/kg) protected the spinal cord neurovasculature after SCI by increasing tight junction protein expression and reducing inflammatory enzyme expression. Improvements in vascular integrity were associated with changes in spinal cord inflammation. Interestingly, hIgG (2 g/kg) increased serum expression of inflammatory cytokines and co-localized (without decreasing protein expression) with spinal cord vascular cell adhesion molecule-1, a protein used by immune cells to enter into inflamed tissue. Acute molecular benefits of hIgG (2 g/kg) led to greater tissue preservation, functional blood flow, and neurobehavioral recovery at 6 weeks post-SCI. Importantly, the effects of hIgG (2 g/kg) were superior to control buffer and hIgG (0.4 g/kg), and comparable with MPSS (0.03 g/kg). CONCLUSIONS: hIgG (2 g/kg) is a promising therapeutic approach to mitigate secondary pathology in SCI through antagonizing immune cell infiltration at the level of the neurovascular unit.


Assuntos
Imunoglobulinas Intravenosas/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Junções Íntimas/efeitos dos fármacos , Animais , Medula Cervical/irrigação sanguínea , Medula Cervical/efeitos dos fármacos , Medula Cervical/patologia , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Distribuição Aleatória , Ratos , Ratos Wistar
15.
Exp Neurol ; 321: 113015, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31326353

RESUMO

Spared corticospinal tract (CST) and proprioceptive afferent (PA) axons sprout after injury and contribute to rewiring spinal circuits, affecting motor recovery. Loss of CST connections post-injury results in corticospinal signal loss and associated reduction in spinal activity. We investigated the role of activity loss and injury on CST and PA sprouting. To understand activity-dependence after injury, we compared CST and PA sprouting after motor cortex (MCX) inactivation, produced by chronic MCX muscimol microinfusion, with sprouting after a CST lesion produced by pyramidal tract section (PTx). Activity suppression, which does not produce a lesion, is sufficient to trigger CST axon outgrowth from the active side to cross the midline and to enter the inactivated side of the spinal cord, to the same extent as PTx. Activity loss was insufficient to drive significant CST gray matter axon elongation, an effect of PTx. Activity suppression triggered presynaptic site formation, but less than PTx. Activity loss triggered PA sprouting, as PTx. To understand injury-dependent sprouting further, we blocked microglial activation and associated inflammation after PTX by chronic minocycline administration after PTx. Minocycline inhibited myelin debris phagocytosis contralateral to PTx and abolished CST axon elongation, formation of presynaptic sites, and PA sprouting, but not CST axon outgrowth from the active side to cross the midline. Our findings suggest sprouting after injury has a strong activity dependence and that microglial activation after injury supports axonal elongation and presynaptic site formation. Combining spinal activity support and inflammation control is potentially more effective in promoting functional restoration than either alone.


Assuntos
Microglia/metabolismo , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Tratos Piramidais/lesões , Recuperação de Função Fisiológica/fisiologia , Animais , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Masculino , Microglia/patologia , Neurônios/patologia , Neurônios Aferentes/metabolismo , Neurônios Aferentes/patologia , Tratos Piramidais/metabolismo , Tratos Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
16.
Eur J Radiol ; 117: 75-88, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31307656

RESUMO

Spinal traumas represent a significant proportion of muscle-skeletal injuries worldwide. Spinal injuries involve a complex structure with components having different traumatic susceptibility and variable healing capabilities. The interaction of numerous variables at time of trauma creates a great variety of lesions which makes challenging the creation and comparison of homogeneous groups, with difficulties in classifying spinal lesions, in assessing their instability, and in defining the indication and outcome of different treatment strategies. The evolution of concepts on instability has accompanied that of traumas classification schemes and treatment strategies. The assessment of instability in a spinal injury is actually crucial in front of newer surgical techniques and hardwares. Despite a long history of attempts to classify spinal traumas, it remains some degree of controversy in describing imaging data and a wide variety of treatment strategies. Acute cervical spine injuries affect from 1.9% to 4.6% of subjects reporting a blunt trauma, and up to 5.9% of multiple-injured patients. Most of spinal cord injuries are a consequence of unstable fractures of the cervical spine. An accurate and early diagnosis is mandatory to prevent neurological damage in unstable fractures. Classic and newer classifications are primarily based on features identifiable by using conventional imaging and CT scan, which are the most available modalities at most trauma centers. Even though multidetector-CT remains superior in assessing with high accuracy bone injuries, MRI is the most sensitive modality for detecting soft tissues injuries and spinal cord damage.


Assuntos
Vértebras Cervicais/lesões , Imagem por Ressonância Magnética , Lesões dos Tecidos Moles/diagnóstico por imagem , Traumatismos da Medula Espinal/diagnóstico por imagem , Traumatismos da Coluna Vertebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Vértebras Cervicais/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Lesões dos Tecidos Moles/classificação , Lesões dos Tecidos Moles/patologia , Traumatismos da Medula Espinal/classificação , Traumatismos da Medula Espinal/patologia , Traumatismos da Coluna Vertebral/classificação , Traumatismos da Coluna Vertebral/patologia , Tomografia Computadorizada por Raios X/métodos
17.
Int Rev Neurobiol ; 146: 103-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349925

RESUMO

Bradykinin is a mediator of vasogenic brain edema formation. Recent reports suggest that bradykinin interacts with nitric oxide synthase (NOS) system in the central nervous system (CNS). However, role of bradykinin in spinal cord injury (SCI) induced alterations in the blood-spinal cord barrier (BSCB), spinal cord blood flow (SCBF), edema formation and cell changes are still not well known. Our previous reports showed that SCI induces marked upregulation of neuronal NOS (nNOS) in the cord associated with BSCB disruption, edema formation and cell injury. Thus, a possibility exists that bradykinin participates in SCI induced nNOS upregulation and cord pathology. To explore this idea a potent bradykinin B2 receptor antagonist HOE-140 was used in our rat model of SCI and cord pathology. SCI was inflicted in Equithesin anesthetized rats by making a longitudinal incision (2mm deep and 5mm long) into the right dorsal horn of the T10-11 segment. The animals were allowed to survive 5h after injury. A focal SCI significantly disrupted BSCB to Evans blue and [131]I-sodium in the traumatized and adjacent segments. Interestingly, far remote spinal cord segments C4 and T5 segments also affected within 5h. These spinal cord segments also exhibited pronounced reductions in the SCBF (mean-30%), increased edematous swelling and profound neuronal damages. Upregulation of nNOS expression is seen in both the dorsal and ventral horns of the spinal cord exhibiting cord pathology. At the ultrastructural level, exudation of lanthanum is seen within the endothelial cell cytoplasm and occasionally in the basal lamina. Pretreatment with low doses of HOE-140 (0. 1mg to 1mg/kg, i.v.) 30min prior to SCI significantly enhanced the SCBF and reduced the BSCB disruption, edema formation, nNOS upregulation and cell injury. However, HOE-140 in doses ranging from 2mg to 5mg/kg, i.v. did not induce significant neuroprotection. These observations are the first to suggest that bradykinin B2 receptors play an important role in BSCB permeability, SCBF, edema formation, nNOS upregulation and cell injury following acute SCI, not reported earlier.


Assuntos
Bradicinina/análogos & derivados , Permeabilidade Capilar/efeitos dos fármacos , Edema/fisiopatologia , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Traumatismos da Medula Espinal/prevenção & controle , Animais , Bradicinina/farmacologia , Relação Dose-Resposta a Droga , Azul Evans/metabolismo , Masculino , Ratos , Iodeto de Sódio/metabolismo , Medula Espinal/irrigação sanguínea , Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Regulação para Cima/efeitos dos fármacos
18.
PLoS One ; 14(7): e0219001, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31265469

RESUMO

This study reports the advantage of a novel technique employing a motorised dental burr to assist laminectomy over the conventional manual technique at T10-T11 vertebra level in a rat model of spinal cord injury. Twenty-four female rats were randomly assigned to four groups: (1) conventionally laminectomised, (2) dental burr assisted laminectomised, (3) conventionally laminectomised with spinal cord contusion and (4) dental burr assisted laminectomised with spinal cord contusion. Basso Beattie Bresnahan (BBB) score, postoperative body weights, rat grimace scale (RGS), open cage activity and rearing was studied at 1, 7, 14, 21 and 28 days postoperatively, and area of spinal tissue affected was evaluated histologically. Laminectomised and spinal cord injured rats from dental burr groups showed significantly more weight gain and less weight loss respectively in comparison with respective conventionally laminectomised groups at various time points. Significantly higher RGS score was noticed in conventionally laminectomised animals on Day 1 in comparison to burr assisted laminectomy and presence of pain was evident until Day 7 in the conventionally spinal cord injured group. BBB score did not differ between techniques, whereas laminectomy groups showed more resting time than spinal injury groups. High rearing score was significantly higher in groups which underwent dental burr assisted technique at various time points with respect to their conventional counterparts. This study suggests that the use of dental burr assisted technique to perform laminectomy will bring refinement by producing less pain, aiding in better recovery, removing procedural artefacts without affecting the outcome of the model.


Assuntos
Laminectomia/métodos , Traumatismos da Medula Espinal/cirurgia , Animais , Peso Corporal , Equipamentos Odontológicos de Alta Rotação , Modelos Animais de Doenças , Desenho de Equipamento , Feminino , Laminectomia/instrumentação , Locomoção , Atividade Motora , Medição da Dor , Ratos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
19.
Int J Mol Sci ; 20(11)2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159345

RESUMO

Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary cellular dysfunctions. The use of mesenchymal stem cells (MSCs) represents one of the most important and promising tested strategies. Their appeal, among the other sources and types of stem cells, increased because of their ease of isolation/preservation and their properties. Nevertheless, encouraging promise from preclinical studies was followed by weak and conflicting results in clinical trials. In this review, the therapeutic role of MSCs is discussed, together with their properties, application, limitations, and future perspectives.


Assuntos
Células-Tronco Mesenquimais/metabolismo , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/metabolismo , Animais , Materiais Biocompatíveis , Biomarcadores , Terapia Baseada em Transplante de Células e Tecidos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Modelos Animais de Doenças , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Fatores de Crescimento Neural/metabolismo , Regeneração Nervosa , Medicina Regenerativa , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia , Regeneração da Medula Espinal , Tecidos Suporte , Pesquisa Médica Translacional
20.
Cell Mol Life Sci ; 76(16): 3141-3156, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31168660

RESUMO

Neurotrauma, a term referencing both traumatic brain and spinal cord injuries, is unique to neurodegeneration in that onset is clearly defined. From the perspective of matrix metalloproteinases (MMPs), there is opportunity to define their temporal participation in injury and recovery beginning at the level of the synapse. Here we examine the diverse roles of MMPs in the context of targeted insults (optic nerve lesion and hippocampal and olfactory bulb deafferentation), and clinically relevant focal models of traumatic brain and spinal cord injuries. Time-specific MMP postinjury signaling is critical to synaptic recovery after focal axonal injuries; members of the MMP family exhibit a signature temporal profile corresponding to axonal degeneration and regrowth, where they direct postinjury reorganization and synaptic stabilization. In both traumatic brain and spinal cord injuries, MMPs mediate early secondary pathogenesis including disruption of the blood-brain barrier, creating an environment that may be hostile to recovery. They are also critical players in wound healing including angiogenesis and the formation of an inhibitory glial scar. Experimental strategies to reduce their activity in the acute phase result in long-term neurological recovery after neurotrauma and have led to the first clinical trial in spinal cord injured pet dogs.


Assuntos
Metaloproteinases da Matriz/metabolismo , Traumatismos da Medula Espinal/patologia , Animais , Axônios/metabolismo , Barreira Hematoencefálica/metabolismo , Hipocampo/metabolismo , Humanos , Bulbo Olfatório/metabolismo , Nervo Óptico/metabolismo , Traumatismos da Medula Espinal/metabolismo , Sinapses/fisiologia
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