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1.
Br J Anaesth ; 123(6): 827-838, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31623841

RESUMO

BACKGROUND: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury. METHODS: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model. RESULTS: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1ß, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist. CONCLUSIONS: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Inflamação/tratamento farmacológico , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Microglia/efeitos dos fármacos , Ratos , Ratos Long-Evans , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia
2.
J Vet Intern Med ; 33(5): 2312-2318, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490026

RESUMO

BACKGROUND: Transcranial magnetic stimulation (TMS) and recording of magnetic motor evoked potentials (MMEP) can detect neurological dysfunction in horses but cutoff values based on confirmed spinal cord dysfunction are lacking. OBJECTIVES: To determine latency time cutoff for neurological dysfunction. ANIMALS: Five control horses and 17 horses with proprioceptive ataxia. METHODS: Case-control study with receiver operating characteristic curve analysis, based on diagnostic imaging, TMS, and histopathological findings. Horses were included if all 3 examinations were performed. RESULTS: Diagnostic imaging and histopathology did not show abnormalities in the control group but confirmed spinal cord compression in 14 of 17 ataxic horses. In the remaining 3 horses, histopathological lesions were mild to severe, but diagnostic imaging did not confirm spinal cord compression. In control horses, latency time values of thoracic and pelvic limbs were significantly lower than in ataxic horses (20 ± 1 vs 34 ± 16 milliseconds, P = .05; and 39 ± 1 vs 78 ± 26 milliseconds, P = .004). Optimal cutoff values to detect spinal cord dysfunction were 22 milliseconds (sensitivity [95% CI interval], 88% [73%-100%]; specificity, 100% [100%-100%]) in thoracic and 40 milliseconds (sensitivity, 94% [83%-100%]; specificity, 100% [100%-100%]) in pelvic limbs. To detect spinal cord dysfunction caused by compression, the optimal cutoff for thoracic limbs remained 22 milliseconds, while it increased to 43 milliseconds in pelvic limbs (sensitivity, 100% [100%-100%]; specificity, 100% [100%-100%] for thoracic and pelvic limbs). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnetic motor evoked potential analysis using these cutoff values is a promising diagnostic tool for spinal cord dysfunction diagnosis in horses.


Assuntos
Potencial Evocado Motor , Doenças dos Cavalos/fisiopatologia , Doenças da Medula Espinal/veterinária , Estimulação Magnética Transcraniana/veterinária , Animais , Ataxia/diagnóstico por imagem , Ataxia/fisiopatologia , Ataxia/veterinária , Estudos de Casos e Controles , Feminino , Doenças dos Cavalos/diagnóstico por imagem , Cavalos , Masculino , Medula Espinal/diagnóstico por imagem , Medula Espinal/fisiopatologia , Compressão da Medula Espinal/diagnóstico por imagem , Compressão da Medula Espinal/fisiopatologia , Compressão da Medula Espinal/veterinária , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/fisiopatologia
3.
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
4.
Biomed Res Int ; 2019: 9628065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467921

RESUMO

The reparative process following spinal cord injury (SCI) is extremely complicated. Cells in the microenvironment express multiple inhibitory factors that affect axonal regeneration over a prolonged period of time. The axon growth inhibitory factor glycogen synthase kinase-3 (GSK-3) is an important factor during these processes. TDZD-8 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) is the most effective and specific non-ATP-competitive inhibitor of GSK-3. Here, we show that administering TDZD-8 after SCI was associated with significantly inhibited neuronal apoptosis, upregulated GAP-43 expression, increased density of cortical spinal tract fibers around areas of injury, and increased Basso, Beattie, and Bresnahan (BBB) scores in the lower limbs. These findings support the notion that GSK-3 inhibitors promote neuronal cell regeneration and lower limb functional recovery.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Regeneração Nervosa/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Tiadiazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Axônios/efeitos dos fármacos , Modelos Animais de Doenças , Proteína GAP-43/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/genética , Humanos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia
5.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454988

RESUMO

Diverse transcriptional controls in the dorsal horn have been observed in pain hypersensitivity. However, the understanding of the exact causes and mechanisms of neuropathic pain development is still fragmentary. Here, the results demonstrated nerve injury decreased the expression of spinal hairy and enhancer of split 1 (Hes1), a transcriptional repressor, and enhanced metabotropic glutamate receptor subtype 5 (mGluR5) transcription/expression, which was accompanied with behavioral allodynia. Moreover, nerve injury decreased Hes1 levels and reciprocally increased cyclin dependent kinase-9 (CDK9) levels and recruited CDK9 to phosphorylate RNA polymerase II (RNAPII) in the promoter fragments of mGluR5, thereby enhancing mGluR5 transcription/expression in the dorsal horn. These effects were also induced by intrathecally administering naïve rats with Hes1 small interfering RNA (siRNA). Conversely, Hes1 overexpression using intrathecal lentiviral vectors in nerve injury rats produced reversal of pain behavior and reversed protein expressions, phosphorylation, and coupling to the promoter segments in the dorsal horn. Collectively, the results in this study indicated nerve injury diminishes spinal Hes1-dependent suppression of CDK9-dependent RNAPII phosphorylation on the mGluR5 promoter that possibly enhances mGluR5 transcription/expression for neuropathic pain development.


Assuntos
Quinase 9 Dependente de Ciclina/metabolismo , Neuralgia/etiologia , Neuralgia/metabolismo , RNA Polimerase II/metabolismo , Receptor de Glutamato Metabotrópico 5/genética , Medula Espinal/metabolismo , Fatores de Transcrição HES-1/genética , Animais , Comportamento Animal , Modelos Animais de Doenças , Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Fenótipo , Regiões Promotoras Genéticas , Ligação Proteica , Ratos , Medula Espinal/fisiopatologia , Fatores de Transcrição HES-1/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética
6.
Neurosci Lett ; 708: 134358, 2019 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-31269465

RESUMO

Rodent models of contusion spinal cord injury (SCI) are widely studied for the mechanisms underlying functional deficits after SCI. Yet, how does lesion level affect SCI-induced motor and sensory dysfunctions remains unclear. Using a computer-controlled impactor (Impact One™, Leica) and the same parameters (diameter, 2.0 mm; Speed: 4.0 m/s; Depth: 1.5 mm; Dwell time: 0.1 s), we produced contusions at mid-thoracic (T10) and rostral-lumbar (L2) spinal cord in male rats, and compared locomotor and sensory dysfunctions within the same experimental setting. The time courses of locomotor deficit were comparable between thoracic (n = 8) and lumbar (n = 7) SCI rats, but the severity was greater after thoracic SCI especially during the first week post-injury, as indicated by the lower Basso, Beattle and Bresnahan open-field locomotion scores. Both groups showed similar heightened avoiding response (hyper-reactivity) to mechanical stimulation applied at the hindpaws from day 21-56 post-injury, as indicated by decreased paw withdrawal thresholds. Compared to lumbar SCI, thoracic SCI induced a greater decrease of paw withdrawal latency in hot-plate test from day 28-56 post-injury. In contrast, lumbar SCI rats showed a greater reduction of avoidance threshold to mechanical stimulation at the girdle region, and larger overgroomed area than thoracic SCI rats at day 14 post-injury. Thus, thoracic SCI may induce greater motor deficits and hindpaw heat hyper-reactivity than did lumbar SCI. In contrast, lumbar SCI may elicit greater at-level mechanical hyper-reactivity and overgrooming behavior than thoracic SCI. Future study needs to examine the specific pathological changes underlying different dysfunctions in two SCI models.


Assuntos
Contusões/fisiopatologia , Atividade Motora , Sensação , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Aprendizagem da Esquiva , Contusões/psicologia , Região Lombossacral , Masculino , Limiar da Dor , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/psicologia , Tórax
7.
Spine (Phila Pa 1976) ; 44(19): E1112-E1121, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31261268

RESUMO

STUDY DESIGN: A controlled, randomized, animal study. OBJECTIVE: The aim of this study was to investigate the role of src-family kinases/p38 pathway in a rat model of lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: LDH always generates radicular pain, and the mechanism remains unclear. We have reported that spinal src-family kinases (SFKs) may be involved in the process, but the downstream mechanism needs further investigation. METHODS: LDH was induced by implantation of autologous nucleus pulposus (NP), harvest from the tail, in lumbar 4/5 spinal nerve roots of rat. Von Frey filaments and radiant heat tests were performed to determine mechanical and thermal pain threshold respectively. Basso, Beattie, and Bresnahan (BBB) scale was assessed to test the locomotor function. The protein level of p-SFKs, t-SFKs, p-p38, t-p38 in spinal cord was examined by western blotting analysis. Cellular location of p-p38 was determined by immunochemistry staining. Spinal tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, and IL-6 levels were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Rats with NP implantation showed persistent ipsilateral mechanical allodynia and thermal hyperalgesia, which manifested as obvious decrease of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). BBB scale indicated the locomotor function of hindpaws in rats with NP implantation kept intact. Western blotting and immunohistochemistry staining revealed that phosphorylated SFKs (p-SFKs) and phosphorylated p38 MAPK (p-p38) were sequentially upregulated in ipsilateral spinal dorsal horn, but not in contralateral side of rats with NP. Intrathecal delivery of SFKs inhibitor reduced spinal p-p38 expression. Both SFKs and p38 inhibitors alleviated pain behaviors in a dose-responsive manner without disturbing locomotor function and reduced spinal expression of TNF-α, IL-1ß, and IL-6 in rats with NP. CONCLUSION: Spinal SFKs contribute to radicular pain by activation of p38 MAPK and increasing pro-inflammatory cytokines expression in rats with NP implantation. Targeting SFKs/p38 pathway may be helpful for alleviating radicular pain. LEVEL OF EVIDENCE: N/A.


Assuntos
Citocinas/metabolismo , Deslocamento do Disco Intervertebral , Medula Espinal , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases da Família src/metabolismo , Animais , Dor nas Costas/metabolismo , Dor nas Costas/fisiopatologia , Modelos Animais de Doenças , Deslocamento do Disco Intervertebral/metabolismo , Deslocamento do Disco Intervertebral/fisiopatologia , Vértebras Lombares/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Ratos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
8.
Curr Opin Anaesthesiol ; 32(5): 668-673, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31343465

RESUMO

PURPOSE OF REVIEW: Persistent postoperative pain (PPP) is a significant source of morbidity in our population. An excellent opportunity to understand the transition from acute to chronic pain states. Understanding the mechanisms that drive this and modulators that influence this transition is essential to both prevent and manage this condition. RECENT FINDINGS: Although the exact mechanism for the development of PPP is still poorly understood, hypotheses abound. Basic science research with animal models implicates nociceptive and neuropathic pain signals leading to pain sensitization due to persistent noxious signaling. Effects on the inhibitory modulation of noxious signaling in medullary-spinal pathways and descending modulation have also been implicated. SUMMARY: Persistent maladaptive neuroplastic changes secondary to neurotrophic factors and interactions between neurons and microglia may well explain the phenomenon. This article reviews the current thought processes on mechanisms and modulators from a basic science and epidemiological perspective.


Assuntos
Dor Crônica/etiologia , Neuralgia/etiologia , Nociceptividade/fisiologia , Dor Pós-Operatória/etiologia , Animais , Dor Crônica/fisiopatologia , Dor Crônica/terapia , Modelos Animais de Doenças , Humanos , Bulbo/citologia , Bulbo/fisiopatologia , Microglia/fisiologia , Vias Neurais/citologia , Vias Neurais/fisiopatologia , Neuralgia/fisiopatologia , Neuralgia/terapia , Neurônios/fisiologia , Dor Pós-Operatória/fisiopatologia , Dor Pós-Operatória/terapia , Medula Espinal/citologia , Medula Espinal/fisiopatologia , Fatores de Tempo
9.
Med Biol Eng Comput ; 57(9): 1843-1860, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31209711

RESUMO

This article shows the design of a robust second-order sliding mode controller to solve the trajectory tracking problem of an active orthosis for assisting back physiotherapies. The orthosis was designed in agreement with morphological dimensions and its articulations distribution followed the same designing rules. The orthosis has six articulated arms attached to an articulated column. The orthosis was fully instrumented with actuators and position sensors at each articulation. The controller implemented a class of hybrid/position controller depending on the relative force exerted by the patient and the orthosis movement. The position information provided by each articulation was supplied to a distributed super-twisting differentiator to recover the corresponding angular velocity. A set of twisting controllers was implemented to regulate the position of the robot in agreement to predefined reference trajectories. Reference trajectories were obtained from a biomechanical-based analysis. The hybrid tracking control problem solved the automation of the assisted therapy to the patient, including the force feedback. The performance of the orthosis was tested with different dummy bodies with different resistance. The robust output feedback controller successfully tracked the reference trajectories despite the material of the dummy used during the testing. The orthosis was evaluated with two volunteers using a simple reference trajectory. Graphical Abstract General structure of the active back assisted orthosis.


Assuntos
Aparelhos Ortopédicos , Modalidades de Fisioterapia/instrumentação , Medula Espinal/fisiopatologia , Simulação por Computador , Desenho de Equipamento , Retroalimentação , Humanos , Modelos Teóricos , Robótica/instrumentação , Robótica/métodos , Software , Medula Espinal/fisiologia
10.
Pain Physician ; 22(3): E215-E224, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31151344

RESUMO

BACKGROUND: Approximately 30% to 80% of patients with brachial plexus avulsion (BPA) developed neuropathic pain. It is an intolerable neuropathic pain, which brings heavy burden to family and society. In addition to motor and sensory deficits, neuropathic pain can be another serious sequela that equally influences the patient. The development of a microsurgical technique has promoted the treatment and rehabilitation of brachial plexus injury, but pain relief after BPA is still a difficult problem. OBJECTIVES: The present study aimed to semi-quantify changes in the behavior, spinal cord and cerebral metabolism in a neuropathic pain model following BPA injury in rats. STUDY DESIGN: Controlled animal study. SETTING: Institute of Rehabilitation Medicine, Shanghai, China. METHODS: A total of 15 Sprague-Dawley rats, weighing 200 to 220 g, were randomly divided into 2 groups: experimental group (n = 10) and control group (n = 5). In the experimental group, neuropathic pain induced by BPA was established by directly avulsing the C5, C6, C7, C8, and T1 roots on the right side from the spinal cord. Rats in the control group only received open-close surgery. The autotomic behavior of biting their own digits was recorded and scored at 2 months after the surgery. Small animal positron emission tomography/computed tomography (PET/CT) images after injection of a 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) tracer were acquired to evaluate glucose metabolism in pain-related brain regions before and after the surgery, respectively. Semi-quantitative values of cortical to cerebellum standardized uptake value (SUV) ratios were calculated. Then, the animals were euthanized and the cervical segments of the spinal cord were removed for detection of glial fibrillary acidic protein (GFAP) expression in the astrocytes by immunohistochemical assay. RESULTS: Nine of the 10 rats (90%) in the experimental group showed autotomic behavior at 2 months after the surgery. Slight autotomic behavior was noted only in one of 5 rats (20%) from the control group. The autotomic score in the experimental group was significantly higher than that in the control group (5.4 ± 1.0 vs. 0.2 ± 0.4, P < 0.05). The experimental group showed significantly higher SUV ratio in both the right and left thalamus, compared to the control group (P < 0.05). Immunohistochemical assay demonstrated that GFAP positive astrocytes in the dorsal horn at the injured side significantly increased compared to the control group (P < 0.05). LIMITATIONS: There are differences between small animals and human beings, and the structure and function of the human brain is more complex than in rodents. Therefore, extrapolation of the present conclusion should be cautious. CONCLUSIONS: The present study reported a unique model of neuropathic pain following total BPA in rodents, which was demonstrated by a higher rate and score of autotomic behavior. More astrocytes were found activated in the spinal cord at the corresponding level of C5 and C6 spinal cord. In the small animal PET/CT imaging, significantly higher standardized glucose metabolic activity was found in both the right and left thalamus in the experimental group. The present study semi-quantified the neuropathic pain behavior in rats and explored the plastic changes in the spinal and brain metabolism. KEY WORDS: Brachial plexus avulsion, small animal PET/CT, glucose metabolism, neuropathic pain, astrocyte, 18F-FDG.


Assuntos
Encéfalo/metabolismo , Encéfalo/fisiopatologia , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Animais , Plexo Braquial/lesões , Encéfalo/patologia , China , Modelos Animais de Doenças , Masculino , Neuralgia/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia
11.
World Neurosurg ; 129: e607-e613, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158549

RESUMO

BACKGROUND: Iatrogenic spinal cord injury (iSCI) during spinal corrective surgery can result in devastating complications, such as paraplegia or paraparesis. Perioperatively, iSCI often occurs as a direct injury during spinal cord instrumentation placement. Currently, treatment of iSCI remains limited to posttraumatic hypothermia, which has demonstrated some value in recent clinical trials. Here we report the outcomes of preinjury hypothermia initiated preprocedurally and maintained for a considerable time after iSCI. METHODS: Twenty-six female Sprague-Dawley rats were assigned at random to either a normothermic group (36 °C) or a hypothermic group (32 °C) and then underwent a laminectomy procedure at the T8 level. Each group was further divided at random to receive a 200-kdyn force contusive spinal cord injury or a sham impact. Hypothermic rats were then rewarmed after 2 hours of hypothermic treatment. Behavioral scores, temperature profiles, weights, and somatosensory evoked potentials were obtained at baseline and at specified time points after the procedure. RESULTS: The median survival was 42 days for the iSCI hypothermic group and 11 days for the iSCI normothermic group (hazard ratio, 3.82; 95% confidence interval, 1.52-9.57). The probability of survival was significantly higher in the iSCI hypothermic group compared with the iSCI normothermic group (χ2 = 4.18; P = 0.040). The hypothermic group exhibited a higher Basso, Beattie and Bresnahan (BBB) locomotor rating scale score (17 vs. 14; P < 0.01), lower normalized latencies (1.06 ± 0.16 seconds vs. 1.34 ± 0.17 seconds; P = 0.04), and higher peak-to-peak amplitudes (0.32 ± 0.10 µV vs. 0.12 ± 0.09 µV; P = 0.005). CONCLUSIONS: The use of prophylactic hypothermia before iSCI was significantly associated with an increased survival rate, higher BBB scores, and improved neurophysiological measures.


Assuntos
Potenciais Somatossensoriais Evocados/fisiologia , Hipotermia Induzida/métodos , Atividade Motora/fisiologia , Traumatismos da Medula Espinal/prevenção & controle , Medula Espinal/fisiopatologia , Animais , Comportamento Animal/fisiologia , Feminino , Modelos Animais , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/fisiopatologia
12.
Spine (Phila Pa 1976) ; 44(13): E749-E758, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31205164

RESUMO

STUDY DESIGN: A study on shortwave diathermy (SWD) versus no treatment following induced spinal cord injury (SCI) in rats. OBJECTIVE: To investigate the effects of athermal SWD treatment on somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) and hindlimb movements in rats with SCI. SUMMARY OF BACKGROUND DATA: SWD has been proven to improve vascular circulation and reduce inflammation. However, there have been few studies on neuroprotective effect of SWD on SCI. METHODS: Twenty-four female Sprague-Dawley (SD) rats were randomly divided into four groups: sham, SCI, SWD, and intact groups. The SCI model was established using the modified Allen weight-drop method. The SWD group received 15 sessions of athermal SWD treatment over a 3-week period of time at 24 hours after SCI. While the sham group and SCI group received no treatment after surgery. Hindlimb movements were evaluated by the Basso, Beattie, and Bresnahan (BBB) scale before surgery, and on days 1, 7, 14, and 21 after the surgery, respectively. The SEP and MEP measurements were simultaneously performed to detect the responses of neural conduction. RESULTS: The week-by-week BBB scores showed a gradual improvement in the rats of both SCI and SWD groups from the first week to the end of the study; however, the BBB scores of the SWD group were higher than those of the SCI group over the course of 3 weeks. Data from the SEP and MEP measurements showed a significant improvement in the SWD group compared with the SCI group at each time point of observation, with a more prominent increase of amplitude and a more evident reduction of latency. There was a linear correlation between the BBB scores and the latency and amplitude of SEPs or MEPs. CONCLUSION: Athermal SWD treatment might facilitate the recovery of locomotor function and exert neuroprotective effect on the SCI. LEVEL OF EVIDENCE: N/A.


Assuntos
Diatermia/métodos , Potencial Evocado Motor/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Animais , Feminino , Membro Posterior/fisiopatologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/fisiopatologia , Resultado do Tratamento
13.
Glia ; 67(9): 1694-1704, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31106910

RESUMO

Secondary progressive multiple sclerosis (SPMS) is an autoimmune disease of the central nervous system (CNS) characterized by progressive motor dysfunction, sensory deficits, and visual problems. The pathological mechanism of SPMS remains poorly understood. In this study, we investigated the role of microglia, immune cells in the CNS, in a secondary progressive form of experimental autoimmune encephalomyelitis (EAE), the mouse model of SPMS. We induced EAE in nonobese diabetic mice and treated the EAE mice with PLX3397, an antagonist of colony stimulating factor-1 receptor, during secondary progression in order to deplete microglia. The results showed that PLX3397 treatment significantly exacerbated secondary progression of EAE and increased mortality rates. Additionally, histological analysis showed that PLX3397 treatment significantly promoted inflammation, demyelination, and axonal degeneration. Moreover, the number of CD4+ T cells in the spinal cord of EAE mice was expanded due to PLX3397-mediated proliferation. These results suggest that microglia suppressed secondary progression of EAE by inhibiting the proliferation of CD4+ T cells in the CNS.


Assuntos
Encefalomielite Autoimune Experimental/fisiopatologia , Microglia/fisiologia , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Animais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/fisiologia , Proliferação de Células/fisiologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Inflamação/patologia , Inflamação/fisiopatologia , Camundongos Endogâmicos NOD , Microglia/patologia , Esclerose Múltipla Crônica Progressiva/patologia , Medula Espinal/patologia , Medula Espinal/fisiopatologia
14.
World Neurosurg ; 129: e343-e351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31132502

RESUMO

OBJECTIVE: Repair of spinal cord injury (SCI) using peripheral nerve graft (PNG) and acidic fibroblast growth factor (aFGF) has shown promising results in rats and a few human patients, but not in nonhuman primates. The aim of this study was to verify the effective use of PNG and aFGF for repairing incomplete SCI in nonhuman primates. METHODS: Six adult rhesus macaques received spinal cord hemisection at T8 level and were grouped into repair and control groups (n = 3 in each). Animals in the repair group underwent nerve repair with autologous PNG plus aFGF immediately after lesioning. The control group received exactly the same operation for lesioning but no treatment. Postoperative behavioral evaluations, electrophysiologic tests (including motor and somatosensory evoked potentials), and magnetic resonance imaging were performed and compared between the 2 groups as well as histologic examination of the spinal cord cephalic to, at, and caudal to the lesion site after sacrifice. RESULTS: Animals in the repair group had better motor function in the lower limbs at every observed time point and demonstrated more improvement on electrophysiologic examinations than the control group. The repair group had smaller areas of myelomalacia on magnetic resonance imaging around the lesion compared with the control group, suggesting diminished inflammatory responses with the repair strategy. CONCLUSIONS: PNG plus aFGF for SCI in nonhuman primates yielded improvements in clinical behavior, electrophysiologic tests, and magnetic resonance imaging. This study suggests that the repair strategy is feasible and effective for nonhuman primate SCI. Further investigations are warranted to corroborate its effectiveness for clinical application.


Assuntos
Fator 1 de Crescimento de Fibroblastos/uso terapêutico , Regeneração Nervosa/fisiologia , Transferência de Nervo/métodos , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/terapia , Animais , Potencial Evocado Motor/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Macaca mulatta , Masculino , Modelos Animais , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/cirurgia
15.
Biomed Pharmacother ; 116: 109019, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146112

RESUMO

A novel type of programmed necrosis called necroptosis has been identified in the field of cell death, thereby offering an opportunity for re-examining necrosis after spinal cord injury (SCI). Several recent studies have suggested receptor-interacting protein kinase 3 (RIP3) plays an important role in necrosis in many cell types. However, it is still unclear what downstream events that lead to cell death are triggered by RIP3 activation. Hence, link between RIP3 inhibition and induction of neuronal cell death via mitochondrial function and antioxidative capacity after SCI was studied in our work. We examined the protective effects of RIP3 inhibition in SCI-mice. Furthermore, mimicking the pathological conditions of SCI in vitro, spinal cord neurons were subjected to oxygen-glucose deprivation. Notably, we found GSK872 and Nec-1 ameliorated the locomotor function and spinal cord edema, and conferred reverse of SCI-induced loss of mitochondrial integrity, ATP, glutathione and superoxide dismutase and elevation of reactive oxygen species and malonyldialdehyde in SCI-mice. Moreover, GSK872 alleviated OGD-inducted mitochondrial dysfunction, decreased antioxidative capacity and cell death in spinal cord neurons, through inhibiting RIP3 activity. The data suggest improving antioxidative capacity as a potential multifunctional treatment after SCI and the broader possibility of targeting RIP3 activity as a therapeutic window for spinal neuroprotective intervention.


Assuntos
Antioxidantes/metabolismo , Locomoção , Mitocôndrias/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/análise , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Animais , Benzotiazóis/farmacologia , Citoproteção/efeitos dos fármacos , Edema/complicações , Edema/patologia , Edema/fisiopatologia , Feminino , Imidazóis/farmacologia , Indóis/farmacologia , Camundongos Endogâmicos C57BL , Quinolinas/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/complicações
16.
Neurol Res ; 41(9): 780-790, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31092134

RESUMO

Objectives-Elevated protein O-GlcNAcylation could benefit cell survival and promote organ functional recovery. Thiamet-G (O-GlcNAcase inhibitor) could upregulate protein O-GlcNAcylation level to improve dyskinesia in models of neurodegenerative diseases without any obvious detrimental side-effects. Therefore, we conducted this study to investigate the effects of protein O-GlcNAcylation upregulation by Thiamet-G on the spinal cord injury (SCI) in rats. Methods-We randomly assigned 74 rats to three groups: sham-operated group (Sham) with no lesion (n = 22), injured control group (SCI+SS) with saline solution (n = 26), and Thiamet-G treated group (SCI+Thiamet-G) (n = 26). We assessed Locomotor behavior using the Basso, Beattice, and Bresnahan (BBB) scale and evaluated histopathological alterations by morphometry and histochemistry. We also assessed potential inflammatory effects by microglia/macrophages immunohistochemistry, and potential apoptosis effects by caspase-3 western blot. Results-Thiamet-G treatment improved hindlimb motor functional recovery by inducing elevated protein O-GlcNAcylation, and mitigated the severity, reduced the lesion size and promoted the structural recovery of the injured spinal cord. Thiamet-G treatment also inhibited microglia/macrophages infiltration at the injury sites and the caspase-3 mediated apoptosis pathway. Discussion-We conclude that Thiamet-G induced elevated protein O-GlcNAcylation to ameliorate acute SCI, which could provide a potential novel therapeutic approach for SCI treatment.


Assuntos
Atividade Motora/efeitos dos fármacos , Piranos/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/patologia , Tiazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Microglia/efeitos dos fármacos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/patologia
17.
Cell Tissue Res ; 377(2): 125-151, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31065801

RESUMO

Axonal regeneration and formation of tripartite (axo-glial) junctions at damaged sites is a prerequisite for early repair of injured spinal cord. Transplantation of stem cells at such sites of damage which can generate both neuronal and glial population has gained impact in terms of recuperation upon infliction with spinal cord injury. In spite of the fact that a copious number of pre-clinical studies using different stem/progenitor cells have shown promising results at acute and subacute stages, at the chronic stages of injury their recovery rates have shown a drastic decline. Therefore, developing novel therapeutic strategies are the need of the hour in order to assuage secondary morbidity and effectuate improvement of the spinal cord injury (SCI)-afflicted patients' quality of life. The present review aims at providing an overview of the current treatment strategies and also gives an insight into the potential cell-based therapies for the treatment of SCI.


Assuntos
Células-Tronco Neurais/transplante , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Medula Espinal/fisiopatologia , Animais , Humanos , Recuperação de Função Fisiológica , Regeneração da Medula Espinal
18.
Neural Plast ; 2019: 2098083, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984253

RESUMO

Although referred pain or hypersensitivity has been repeatedly reported in irritable bowel syndrome (IBS) patients and experimental colitis rodents, little is known about the neural mechanisms. Spinal long-term potentiation (LTP) of nociceptive synaptic transmission plays a critical role in the development of somatic hyperalgesia in chronic pain conditions. Herein, we sought to determine whether spinal LTP contributes to the referral hyperalgesia in colitis rats and particularly whether electroacupuncture (EA) is effective to alleviate somatic hyperalgesia via suppressing spinal LTP. Rats in the colitis group (induced by colonic infusion of 2,4,6-trinitrobenzenesulfonic acid, TNBS), instead of the control and vehicle groups, displayed evident focal inflammatory destruction of the distal colon accompanied not only with the sensitized visceromotor response (VMR) to noxious colorectal distension (CRD) but also with referral hindpaw hyperalgesia indicated by reduced mechanical and thermal withdrawal latencies. EA at Zusanli (ST36) and Shangjuxu (ST37) attenuated the severity of colonic inflammation, as well as the visceral hypersensitivity and referral hindpaw hyperalgesia in colitis rats. Intriguingly, the threshold of C-fiber-evoked field potentials (CFEFP) was significantly reduced and the spinal LTP was exaggerated in the colitis group, both of which were restored by EA treatment. Taken together, visceral hypersensitivity and referral hindpaw hyperalgesia coexist in TNBS-induced colitis rats, which might be attributed to the enhanced LTP of nociceptive synaptic transmission in the spinal dorsal horn. EA at ST36 and ST37 could relieve visceral hypersensitivity and, in particular, attenuate referral hindpaw hyperalgesia by suppressing the enhanced spinal LTP.


Assuntos
Colite/fisiopatologia , Eletroacupuntura , Hiperalgesia/fisiopatologia , Potenciação de Longa Duração , Nociceptividade/fisiologia , Medula Espinal/fisiopatologia , Animais , Colite/induzido quimicamente , Colite/prevenção & controle , Modelos Animais de Doenças , Membro Posterior/fisiopatologia , Hiperalgesia/complicações , Masculino , Limiar da Dor , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico/administração & dosagem
19.
Neurosci Lett ; 706: 18-23, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31026533

RESUMO

We examined the effect of immobilization, low-intensity muscle contraction exercise, and transcutaneous electrical nerve stimulation (TENS) on tissue inflammation and acute pain following the onset of arthritis in a rat model. Sixty Wistar rats were divided into five groups: (1) Arthritis group, (2) arthritis and immobilization (Immobilization group), (3) arthritis and low intensity muscle contraction (Exercise group), (4) arthritis and TENS (TENS group), and (5) sham arthritis (Sham group). Arthritis was induced in the right knee joints by single injection of 3% kaolin and carrageenan. Immobilization of the right hindlimb was conducted by full extension of the right knee joints and full plantar flexion of the ankle joints using a plaster cast for 7 days after injection. The right quadriceps muscles were subjected to electrical stimulation (frequency: 50 Hz; intensity: 2-3 mA) for 20 min/day as contraction exercise for one week. TENS was delivered at 20 min/day for one week (frequency: 50 Hz; intensity: 1 mA). The pressure pain threshold (PPT) and paw withdrawal response (PWR) were evaluated at 1 and 7 days after injection. We also analyzed the number of CD68-positive cells in the synovium by immunohistochemistry and determined the expression level of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn with immunofluorescence. Improvements of both PPT and PWR were observed in the Exercise group at 7 days after injection compared to those of the Arthritis and Immobilization groups, although only improvement of PPT was observed in the TENS group. The number of CD68-positive cells in the synovium and CGRP expression in the dorsal horn decreased only in the Exercise group. These results suggested that low-intensity muscle contraction exercise might be a better treatment for reduction of arthritis-induced inflammation and acute pain compared to immobilization and TENS.


Assuntos
Artrite Experimental/terapia , Sensibilização do Sistema Nervoso Central/fisiologia , Terapia por Exercício/métodos , Hiperalgesia/terapia , Inflamação/terapia , Contração Muscular/fisiologia , Medula Espinal/fisiopatologia , Animais , Artrite Experimental/fisiopatologia , Hiperalgesia/fisiopatologia , Inflamação/fisiopatologia , Músculo Esquelético/fisiopatologia , Medição da Dor , Limiar da Dor/fisiologia , Ratos , Ratos Wistar , Estimulação Elétrica Nervosa Transcutânea
20.
Dokl Biol Sci ; 484(1): 5-9, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31016495

RESUMO

When studying a preparation of the isolated spinal cord segment of an adult frog, damaged and intact lumbar motoneurons were found to differ significantly in the membrane potential, input resistance and the action potential properties (amplitude, duration, fast and medium phases of the afterhyperpolarization, and the frequency of spikes). Serotonin (5-HT) reduced the amplitude of afterpolarization and increased the frequency of the spikes of the intact neurons, while in the damaged motoneurons, 5-HT increased the amplitude of afterpolarization and had no effect on the frequency of discharges.


Assuntos
Neurônios Motores/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/efeitos dos fármacos , Potenciais de Ação , Animais , Neurônios Motores/fisiologia , Ranidae , Medula Espinal/fisiopatologia
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