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1.
J Neuroinflammation ; 19(1): 129, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35658977

RESUMO

BACKGROUND: Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Microglial activation in the spinal cord plays a critical role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely understood. Here, we investigated the role of Dickkopf (DKK) 3 and its interplay with microglial activation in the spinal cord in neuropathic pain. METHODS: In this study, we investigated the effects of intrathecal injection of recombinant DKK3 (rDKK3) on mechanical allodynia and microglial activation in the spinal cord after spared nerve injury (SNI) in rats by western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that SNI induced a significant decrease in the levels of DKK3, Kremen-1 and Dishevelled-1 (DVL-1) and up-regulated the expression of phosphorylated apoptosis signal-regulating kinase 1 (p-ASK1), phosphorylated c-JUN N-terminal kinase (p-JNK), phosphorylated p38 (p-p38) in the spinal cord. Moreover, our results showed that exogenous intrathecal administration of rDKK3 inhibited expression of p-ASK1, p-JNK, p-p38, promoted the transformation of microglia from M1 type to M2 type, and decreased the production of pro-inflammatory cytokines compared to the rats of SNI + Vehicle. However, these effects were reversed by intrathecal administration of Kremen-1 siRNA or Dishevelled-1 (DVL-1) siRNA. CONCLUSIONS: These results suggest that DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation, at least partly, by the Kremen-1 and DVL-1 pathways.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Microglia , Neuralgia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Hiperalgesia/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Medula Espinal/metabolismo
2.
Ther Hypothermia Temp Manag ; 12(2): 90-102, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35675523

RESUMO

Spinal cord injury (SCI) is a devastating neurological condition with no effective treatment. Hypothermia induced by physical means (cold fluid) is established as an effective therapy in animal models of SCI, but its clinical translation to humans is hampered by several constraints. Hypothermia induced pharmacologically may be noninferior or superior to physically induced hypothermia for rapid, convenient systemic temperature reduction, but it has not been investigated previously in animal models of SCI. We used a rat model of SCI to compare outcomes in three groups: (1) normothermic controls; (2) hypothermia induced by conventional physical means; (3) hypothermia induced by intravenous (IV) dihydrocapsaicin (DHC). Male rats underwent unilateral lower cervical SCI and were treated after a 4-hour delay with physical cooling or IV DHC (∼0.60 mg/kg total) cooling (both 33.0 ± 1.0°C) lasting 4 hours; controls were kept normothermic. Telemetry was used to monitor temperature and heart rate during and after treatments. In two separate experiments, one ending at 48 hours, the other at 6 weeks, "blinded" investigators evaluated rats in the three groups for neurological function followed by histopathological evaluation of spinal cord tissues. DHC reliably induced systemic cooling to 32-33°C. At both the time points examined, the two modes of hypothermia yielded similar improvements in neurological function and lesion size compared with normothermic controls. Our results indicate that DHC-induced hypothermia may be comparable with physical hypothermia in efficacy, but more clinically feasible to administer than physical hypothermia.


Assuntos
Hipotermia Induzida , Hipotermia , Traumatismos da Medula Espinal , Animais , Capsaicina/análogos & derivados , Hipotermia/terapia , Hipotermia Induzida/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia
3.
Contrast Media Mol Imaging ; 2022: 6551358, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35655729

RESUMO

Nervous inflammation is an important component of the pathogenesis of neurodegenerative diseases including chronic diabetic neuropathic pain. In order to obtain a decrease in the progression of diabetic neuronal damage, it may be necessary to examine therapeutic options that involve antioxidants and anti-inflammatory agents. The aim of this study was to investigate the attenuation of inflammatory factors with endurance training in the spinal cord of rats with neuropathic pain. Thirty-two 8-week-old male Wistar rats (with a weight range of 204 ± 11.3 g) were randomly divided into 4 groups (n = 8), including (1) diabetic neuropathy (50 mg/kg streptozotocin intraperitoneal injection), (2) diabetic neuropathy training (30 minutes of endurance training at 15 meters per minute, 5 days a week for 6 weeks), (3) healthy training, and (4) healthy control. After confirmation of diabetic neuropathy by behavioral tests, training protocol and supplementation were performed. The NLRP3, P38 MAPK, TNF-α, and IL-1ß gene expressions were measured by a real-time technique in the spinal cord tissue. One-way analysis of variance and Tukey's post hoc test were used for statistical analysis. Endurance training reduced the sensitivity of the nervous system to thermal hyperalgesia and mechanical allodynia; also, compared to the diabetic neuropathy group, the gene expressions of NLTP3, P38 MAPK, TNF-α, and IL-1ß were significantly reduced by endurance training (P < 0.05). Endurance training modulates NLRP3, P38 MAPK, and TNF-α, IL-1ß gene expressions and improves the sensitivity of nociceptors to pain factors. Accordingly, it is recommended to use endurance training to reduce neuropathic pain for diabetics.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Treino Aeróbico , Neuralgia , Animais , Biomarcadores/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Ratos , Ratos Wistar , Medula Espinal , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/uso terapêutico
4.
BMC Med Imaging ; 22(1): 107, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35659198

RESUMO

BACKGROUND: Diffusion tensor imaging (DTI) was used to quantitatively study the characteristics of the related spinal cord and nerve root compression parameters in patients with cervical spondylosis (CS), and diffusion tensor tractography (DTT) was used to visualize the spinal cord and nerve root and analyze their relevance to clinical evaluation. METHODS: A total of 67 patients with CS and 30 healthy volunteers received 3.0 T magnetic resonance imaging. Cervical DTI and DTT were performed in all the participants, where the b value of DTI was set at 800 s/mm2. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of the spinal cord and cervical nerve roots were measured by using DTI. Patients with CS were scored according to the modified Japanese Orthopedic Association (mJOA) score. RESULTS: In all the participants, the spinal cord and cervical nerve roots were clearly visible by DTT. Compared to the healthy volunteers, the FA values were significantly decreased and ADC values were significantly increased in patients with CS. mJOA score was significantly correlated with the DTI index (ADC and FA) values. Receiver operator characteristic curve analysis revealed that FA and ADC could identify mild, moderate, and severe CS. CONCLUSIONS: DTI parameters of cervical spinal cord and nerve root compression are associated with the clinical evaluation of patients with CS and may be helpful in assessing the severity of CS.


Assuntos
Medula Cervical , Radiculopatia , Espondilose , Medula Cervical/diagnóstico por imagem , Medula Cervical/patologia , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/patologia , Imagem de Tensor de Difusão/métodos , Humanos , Radiculopatia/complicações , Radiculopatia/patologia , Medula Espinal , Espondilose/diagnóstico por imagem , Espondilose/patologia
5.
J Neuroinflammation ; 19(1): 160, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35725619

RESUMO

BACKGROUND: Spinal cord injury (SCI) causes devastating neurological damage, including secondary injuries dominated by neuroinflammation. The role of Apelin, an endogenous ligand that binds the G protein-coupled receptor angiotensin-like receptor 1, in SCI remains unclear. Thus, our aim was to investigate the effects of Apelin in inflammatory responses and activation of endogenous neural stem cells (NSCs) after SCI. METHODS: Apelin expression was detected in normal and injured rats, and roles of Apelin in primary NSCs were examined. In addition, we used induced pluripotent stem cells (iPSCs) as a carrier to prolong the effective duration of Apelin and evaluate its effects in a rat model of SCI. RESULTS: Co-immunofluorescence staining suggested that Apelin was expressed in both astrocytes, neurons and microglia. Following SCI, Apelin expression decreased from 1 to 14 d and re-upregulated at 28 d. In vitro, Apelin promoted NSCs proliferation and differentiation into neurons. In vivo, lentiviral-transfected iPSCs were used as a carrier to prolong the effective duration of Apelin. Transplantation of transfected iPSCs in situ immediately after SCI reduced polarization of M1 microglia and A1 astrocytes, facilitated recovery of motor function, and promoted the proliferation and differentiation of endogenous NSCs in rats. CONCLUSION: Apelin alleviated neuroinflammation and promoted the proliferation and differentiation of endogenous NSCs after SCI, suggesting that it might be a promising target for treatment of SCI.


Assuntos
Traumatismos da Medula Espinal , Animais , Apelina/metabolismo , Diferenciação Celular/fisiologia , Proliferação de Células , Ratos , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo
6.
Sci Rep ; 12(1): 10151, 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710920

RESUMO

MRI is the primary diagnostic modality for spinal cord tumors. However, its validity has never been vigorously scrutinized in daily routine clinical practice, where MRI tissue diagnosis is usually not a single one but multiple ones with several differential diagnoses. Here, we aimed to assess the validity of MRI in terms of predicting the pathology and location of the tumor in routine clinical settings. We analyzed 820 patients with primary spinal cord tumors, who have a pathological diagnosis and location in the operation record which were confirmed. We modified traditional measures for validity based upon a set of diagnoses instead of a single diagnosis. Sensitivity and specificity and positive and negative predictabilities were evaluated for the tumor location and pathology. For tumor location, 456 were intradural extramedullary; 165 were intramedullary, and 156 were extradural. The overall sensitivity and specificity were over 90.0%. However, the sensitivity became lower when the tumor resided simultaneously in two spaces such as in the intradural-and-extradural or intramedullary-and-extramedullary space (54.6% and 30.0%, respectively). Most common pathology was schwannoma (n = 416), followed by meningioma (114) and ependymoma (87). Sensitivities were 93.3%, 90.4%, and 89.7%, respectively. Specificities were 70.8%, 82.9%, and 76.0%. In rare tumors such as neurofibromas, and diffuse midline gliomas, the sensitivity was much lower (less than 30%). For common locations and pathologies, the validity of MRI is generally acceptable. However, for rare locations and pathologies, MRI diagnosis still needs some improvement.


Assuntos
Ependimoma , Neoplasias Meníngeas , Meningioma , Neoplasias da Medula Espinal , Ependimoma/patologia , Humanos , Imageamento por Ressonância Magnética , Meningioma/diagnóstico , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/patologia
7.
J Radiol Case Rep ; 16(5): 1-9, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35711686

RESUMO

Neurobrucellosis is an uncommon serious complication of brucellosis. Diagnosis of neurobrucellosis could be difficult due to non-specific clinical and radiological findings. So, in endemic regions, neurobrucellosis should be included in the differential diagnosis list of patients with recent neurological disorders. We report an unusual case of neurobrucellosis with neurologic deficits in the central and peripheral nervous system and MRI lesions in the brainstem, spinal cord, and nerve roots Also, related articles are reviewed in the discussion section.


Assuntos
Brucelose , Cauda Equina , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/patologia , Brucelose/complicações , Brucelose/diagnóstico por imagem , Brucelose/tratamento farmacológico , Cauda Equina/diagnóstico por imagem , Cauda Equina/patologia , Cerebelo , Humanos , Imageamento por Ressonância Magnética , Medula Espinal/diagnóstico por imagem
8.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 36(6): 751-759, 2022 Jun 15.
Artigo em Chinês | MEDLINE | ID: mdl-35712934

RESUMO

Objective: To investigate the effect of M2-like macrophage/microglia-derived mitochondria transplantation in treatment of mouse spinal cord injury (SCI). Methods: BV2 cells were classified into M1 (LPS treatment), M2 (IL-4 treatment), and M0 (no treatment) groups. After receiving M1 and M2 polarization, BV2 cells received microscopic observation, immunofluorescence staining [Arginase-1 (Arg-1)] and flow cytometry [inducible nitric oxide synthase (iNOS), Arg-1] to determine the result of polarization. MitoSox Red and 2, 7-dichlorodi-hydrofluorescein diacetate (DCFH-DA) stainings were used to evaluate mitochondrial function difference. Mitochondria was isolated from M2-like BV2 cells through differential velocity centrifugation for following transplantation. Then Western blot was used to measure the expression levels of the relevant complexes (complexes Ⅱ, Ⅲ, Ⅳ, and Ⅴ) in the oxidative phosphorylation (OXPHOS), and compared with M2-like BV2 cells to evaluate whether the mitochondria were obtained. Thirty-six female C57BL/6 mice were randomly divided into 3 groups ( n=12). Mice from sham group were only received the T 10 laminectomy. After the T 10 spinal cord injury (SCI) model was prepared in the SCI group and mitochondria transplantation (MT) group, mitochondrial storage solution and mitochondria (100 µg) derived from M2-like BV2 cells were injected into the injured segment, respectively. After operation, the Basso Mouse Scale (BMS) score was performed to evaluate the motor function recovery. And immunofluorescence staining, lycopersicon esculentum agglutinin (LEA)-FITC staining, and ELISA [vascular endothelial growth factor A (VEGFA)] were also performed. Results: After polarization induction, BV2 cells in M1 and M2 groups showed specific morphological changes of M1-like and M2-like macrophages, respectively. Immunofluorescence staining showed that the positive expression of M2-like macrophages marker (Arg-1) was significantly higher in M2 group than in M0 group and M1 group ( P<0.05). Flow cytometry showed that the expression of M1-like macrophage marker (iNOS) was significantly higher in M1 group than in M0 group and M2 group ( P<0.05), and the expression of Arg-1 was significantly higher in M2 group than in M0 group and M1 group ( P<0.05). MitoSox Red and DCFH-DA stainings showed that the fluorescence intensity of the M2 group was significantly lower than that of the M1 group ( P<0.05), and there was no significant difference with the M0 group ( P>0.05). The M2-like BV2 cells-derived mitochondria was identified through Western blot assay. Animal experiments showed that the BMS scores of MT group at 21 and 28 days after operation were significantly higher than those of SCI group ( P<0.05). At 14 days after operation, the number of iNOS-positive cells in MT group was significantly lower than that in SCI group ( P<0.05), but still higher than that in sham group ( P<0.05); the number of LEA-positive cells and the expression of VEGFA in MT group were significantly more than those in the other two groups ( P<0.05). Conclusion: M2-like macrophage/microglia-derived mitochondria transplantation can promote angiogenesis and inhibit inflammatory M1-like macrophage/microglia polarization after mouse SCI to improve function recovery.


Assuntos
Microglia , Traumatismos da Medula Espinal , Animais , Feminino , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/terapia , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Neurosurg Clin N Am ; 33(3): 287-295, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35718398

RESUMO

The efficacy of spinal cord stimulation for treating chronic pain has encouraged the development of a wide variety of different technologies for stimulation. In this review, the authors first discuss how parameters of stimulation determine the stimulation waveform. They then discuss new stimulation waveforms, including high frequency and burst stimulation, and the evidence supporting their use. Finally, the authors turn to emerging technologies and techniques including dorsal root ganglion stimulation, wireless stimulation, and closed-loop stimulation.


Assuntos
Dor Crônica , Estimulação da Medula Espinal , Dor Crônica/terapia , Gânglios Espinais , Humanos , Medula Espinal , Estimulação da Medula Espinal/métodos , Tecnologia
10.
Neurosurg Clin N Am ; 33(3): 297-303, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35718399

RESUMO

Most currently available neuromodulation techniques for pain work through an open-loop system. The distance between the epidural space and the target of the stimulation in a dynamic body can change because of physiologic conditions. The closed-loop system in spinal cord neuromodulation consists of an integrated system that records real-time electrophysiological activity in the form of evoked compound action potentials and uses it in a feedback mechanism to adjust stimulus output. Wearables represent newly developed technologies that have gained traction in recent years. Their application in pain management is still developing but promising.


Assuntos
Estimulação da Medula Espinal , Dispositivos Eletrônicos Vestíveis , Eletrofisiologia , Humanos , Manejo da Dor , Medula Espinal , Estimulação da Medula Espinal/métodos
11.
FASEB J ; 36(7): e22393, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35699080

RESUMO

Spinal cord injury (SCI) results in dynamic alterations of the microenvironment at the lesion site, which inevitably leads to neuronal degeneration and functional impairment. The destruction of the spinal vascular system leads to a significant deterioration of the milieu, which exacerbates inflammatory response and deprives cells of nutrient support in the lesion. Limited endogenous angiogenesis occurs after SCI, but the cellular events at the lesion site during this process are unclear so far. Here, we performed single-cell RNA sequencing (scRNA-seq) on spinal cord tissues of rats at different time points after SCI. After clustering and cell-type identification, we focused on vascular endothelial cells (ECs), which play a pivotal role in angiogenesis, and drew the cellular and molecular atlas for angiogenesis after SCI. We found that microglia and macrophages promote endogenous angiogenesis by regulating EC subsets through SPP1 and IGF signaling pathways. Our results indicate that immune cells promote angiogenesis by regulating specific subsets of vascular ECs, which provides new clues for exploring SCI intervention.


Assuntos
Microglia , Traumatismos da Medula Espinal , Animais , Células Endoteliais/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Ratos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo
12.
Int J Mol Sci ; 23(11)2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35682543

RESUMO

Chronic neuropathic pain emerges from either central or peripheral lesions inducing spontaneous or amplified responses to non-noxious stimuli. Despite different pharmacological approaches to treat such a chronic disease, neuropathic pain still represents an unmet clinical need, due to long-term therapeutic regimens and severe side effects that limit application of currently available drugs. A critical phenomenon involved in central sensitization is the exchange of signalling molecules and cytokines, between glia and neurons, driving the chronicization process. Herein, using a chronic constriction injury (CCI) model of neuropathic pain, we evaluated the efficacy of the mu (M-) and delta (D-) opioid receptor (-OR) targeting agent LP2 in modulating connexin-based heterocellular coupling and cytokine levels. We found that long-term efficacy of LP2 is consequent to MOR-DOR targeting resulting in the reduction of CCI-induced astrocyte-to-microglia heterocellular coupling mediated by connexin 43. We also found that single targeting of DOR reduces TNF and IL-6 levels in the chronic phase of the disease, but the peripheral and central discharge as the primary source of excitotoxic stimulation in the spinal cord requires a simultaneous MOR-DOR targeting to reduce CCI-induced neuropathic pain.


Assuntos
Neuralgia , Receptores Opioides delta , Analgésicos Opioides/farmacologia , Conexina 43/uso terapêutico , Humanos , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptores Opioides , Receptores Opioides mu , Medula Espinal
13.
Int J Mol Sci ; 23(11)2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35682897

RESUMO

Synaptic cell adhesion molecules (SynCAMs) play an important role in the formation and maintenance of synapses and the regulation of synaptic plasticity. SynCAM3 is expressed in the synaptic cleft of the central nervous system (CNS) and is involved in the connection between axons and astrocytes. We hypothesized that SynCAM3 may be related to the astrocytic scar (glial scar, the most important factor of CNS injury treatment) through extracellular matrix (ECM) reconstitution. Thus, we investigated the influence of the selective removal of SynCAM3 on the outcomes of spinal cord injury (SCI). SynCAM3 knock-out (KO) mice were subjected to moderate compression injury of the lower thoracic spinal cord using wild-type (WT) (C57BL/6JJc1) mice as controls. Single-cell RNA sequencing analysis over time, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and immunohistochemistry (IHC) showed reduced scar formation in SynCAM3 KO mice compared to WT mice. SynCAM3 KO mice showed improved functional recovery from SCI by preventing the transformation of reactive astrocytes into scar-forming astrocytes, resulting in improved ECM reconstitution at four weeks after injury. Our findings suggest that SynCAM3 could be a novel therapeutic target for SCI.


Assuntos
Gliose , Traumatismos da Medula Espinal , Animais , Astrócitos/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Cicatriz/patologia , Gliose/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo
14.
J Long Term Eff Med Implants ; 32(2): 81-86, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35695630

RESUMO

The artery of Adamkiewicz (AKA) provides blood supply to the thoracolumbar spinal cord. Any disruption of the AKA can lead to the anterior spinal artery (ASA) syndrome, with devastating systematic and neurologic complications for the patient. This is a narrative review of the anatomy of AKA, the characteristics of ASA syndrome and the role of radiologic techniques in diagnosis and treatment. A detailed search of the PubMed database was conducted from January 2000 until April 2020, to locate articles relevant to our study. The references of the included studies were also retrieved in order not to miss any information. The ASA syndrome can present as a possible post-operative complication after minimally invasive or open surgeries of multiple specialties that involve the field of spine. Risk factors associated with ASA syndrome include; kyphosis of the patient, corresponding spinal surgical approach, intraoperative hypotension, multiple ligations of the AKA, a left side approach and a 360-combined or revision surgery. The incidence varies among different operations. Many different imaging modalities have been used in preoperative plan, including but not limited to computed tomography angiography, magnetic resonance angiography, and subtraction angiography. The use of computed tomography angiography or magnetic resonance angiography preoperatively can play a major role in the prevention of the ASA syndrome. However, more research needs to be done before making any final assumptions.


Assuntos
Angiografia , Artérias , Angiografia/métodos , Artérias/diagnóstico por imagem , Humanos , Medula Espinal/irrigação sanguínea , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/cirurgia , Tomografia Computadorizada por Raios X/métodos
15.
PLoS One ; 17(6): e0269924, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35696412

RESUMO

Septic patients commonly present with central nervous system (CNS) disorders including impaired consciousness and delirium. Today, the main mechanism regulating sepsis-induced cerebral disorders is believed to be neuroinflammation. However, it is unknown how another component of the CNS, the spinal cord, is influenced during sepsis. In the present study, we intraperitoneally injected mice with lipopolysaccharide (LPS) to investigate molecular and immunohistochemical changes in the spinal cord of a sepsis model. After LPS administration in the spinal cord, pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha mRNA were rapidly and drastically induced. Twenty-four-hour after the LPS injection, severe neuronal ischemic damage spread into gray matter, especially around the anterior horns, and the anterior column had global edematous changes. Immunostaining analyses showed that spinal microglia were significantly activated and increased, but astrocytes did not show significant change. The current results indicate that sepsis induces acute neuroinflammation, including microglial activation and pro-inflammatory cytokine upregulation in the spinal cord, causing drastic neuronal ischemia and white matter edema in the spinal cord.


Assuntos
Sepse , Animais , Citocinas , Humanos , Lipopolissacarídeos , Camundongos , Microglia , Sepse/patologia , Medula Espinal/patologia
16.
J Neuroinflammation ; 19(1): 134, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35668451

RESUMO

BACKGROUND: Spinal cord injury (SCI) induces a multitude of deleterious processes, including neuroinflammation and oxidative stress (OS) which contributed to neuronal damage and demyelination. Recent studies have suggested that increased formation of reactive oxygen species (ROS) and the consequent OS are critical events associated with SCI. However, there is still little information regarding the impact of these events on SCI. Astrocytes are key regulators of oxidative homeostasis in the CNS and astrocytic antioxidant responses promote the clearance of oxidants produced by neurons. Therefore, dysregulation of astrocyte physiology might largely contribute to oxidative damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of cellular anti-oxidative stress responses. METHODS: In the current study, we hypothesized that astrocytic activation of Nrf2 protects the spinal cord post injury via suppression of neuroinflammation. Thus, using mice line with a GFAP-specific kelch-like ECH-associated protein 1 (Keap1)-deletion, we induced a hyperactivation of Nrf2 in astrocytes and further its effects on SCI outcomes. SCI-induction was performed in mice using the Infinite Horizon Spinal Cord Impactor with a force of 60 kdyn. To assess the quantitative pattern of Nrf2/ARE-activation, we included transgenic ARE-Luc mice. Data were analyzed with GraphPad Prism 8 (GraphPad Software Inc., San Diego, CA, USA). Brown-Forsythe test was performed to test for equal variances and normal distribution was tested with Shapiro-Wilk. RESULTS: In ARE-Luc mice, a significant induction of luciferase-activity was observed as early as 1 day post-injury, indicating a functional role of Nrf2-activity at the epicenter of SCI. Furthermore, SCI induced loss of neurons and oligodendrocytes, demyelination and inflammation in wild type mice. The loss of myelin and oligodendrocytes was clearly reduced in Keap1 KO mice. In addition, Keap-1 KO mice showed a significantly better locomotor function and lower neuroinflammation responses compared to wild type mice. CONCLUSIONS: In summary, our in vivo bioluminescence data showed Nrf2-ARE activation during primary phase of SCI. Furthermore, we found that cell specific hyperactivation of Nrf2 was sufficient to protect the spinal cord against injury which indicate a promising therapeutic approach for SCI-treatment.


Assuntos
Doenças Desmielinizantes , Traumatismos da Medula Espinal , Animais , Astrócitos/metabolismo , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo
17.
Dev Biol ; 488: 114-119, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35644253

RESUMO

Axon regeneration in response to injury has been documented in many animals over several hundred years. In contrast, how neurons respond to dendrite injury has been examined only in the last decade. So far, dendrite regeneration after injury has been documented in invertebrate model systems, but has not been assayed in a vertebrate. In this study, we use zebrafish motor neurons to track neurons after dendrite injury. We address two major gaps in our knowledge of dendrite regeneration: 1) whether post-synaptic dendrites can regenerate and 2) whether vertebrate dendrites can regenerate. We find that motor neurons survive laser microsurgery to remove one or all dendrites. Outgrowth of new dendrites typically initiated one to three days after injury, and a new, stable dendrite arbor was in place by five days after injury. We conclude that zebrafish motor neurons have the capacity to regenerate a new dendrite arbor.


Assuntos
Dendritos , Regeneração da Medula Espinal , Animais , Axônios , Dendritos/fisiologia , Neurônios Motores , Regeneração Nervosa/fisiologia , Medula Espinal , Peixe-Zebra
18.
Neurosci Lett ; 782: 136705, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35660650

RESUMO

Since 1967, spinal cord stimulation (SCS) has been used to manage chronic intractable pain of the trunk and limbs. Low-intensity, paresthesia-free, 10 kHz SCS has demonstrated statistically- and clinically-superior long-term pain relief compared to conventional SCS. 10 kHz SCS has been proposed to operate via selective activation of inhibitory interneurons in the superficial dorsal horn. In contrast, 40 Hz SCS is presumed to operate largely via dorsal column fiber activation. To determine if these mechanisms may be implemented synergistically, we examined the effect of each type of stimulation both independently and simultaneously on putatively inhibitory and putatively excitatory neurons in the superficial dorsal horn. When 10 kHz SCS was applied relatively caudally to the measured spinal segment, simultaneous with 40 Hz SCS applied relatively rostrally to that spinal segment, inhibitory interneurons demonstrated a median increase of 26 spikes/s compared to their baseline firing rates. Median firing rate increases of inhibitory interneurons were 8.7 and 5.1 spikes/s during 40 Hz SCS applied rostrally and 10 kHz SCS applied caudally, respectively. By comparison, the median firing rate of excitatory interneurons increased by 4.1 spikes/s during simultaneous 40 Hz SCS applied rostrally and 10 kHz SCS applied caudally. Median firing rate increases of excitatory interneurons were 13 and 0.8 spikes/s during 40 Hz SCS applied rostrally and 10 kHz SCS applied caudally, respectively. This suggests that simultaneously applying 10 kHz SCS caudally and 40 Hz SCS rostrally may provide greater pain relief than either type of SCS alone by increasing the firing rates of inhibitory interneurons, albeit with greater excitatory interneuron activation.


Assuntos
Dor Crônica , Estimulação da Medula Espinal , Humanos , Interneurônios , Manejo da Dor , Medula Espinal , Corno Dorsal da Medula Espinal
19.
Development ; 149(12)2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35708609

RESUMO

It is well established that humans and other mammals are minimally regenerative compared with organisms such as zebrafish, salamander or amphibians. In recent years, however, the identification of regenerative potential in neonatal mouse tissues that normally heal poorly in adults has transformed our understanding of regenerative capacity in mammals. In this Review, we survey the mammalian tissues for which regenerative or improved neonatal healing has been established, including the heart, cochlear hair cells, the brain and spinal cord, and dense connective tissues. We also highlight common and/or tissue-specific mechanisms of neonatal regeneration, which involve cells, signaling pathways, extracellular matrix, immune cells and other factors. The identification of such common features across neonatal tissues may direct therapeutic strategies that will be broadly applicable to multiple adult tissues.


Assuntos
Coração , Peixe-Zebra , Anfíbios , Animais , Mamíferos , Camundongos , Medula Espinal
20.
Anesth Analg ; 135(1): 178-190, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35709447

RESUMO

BACKGROUND: Spinal cord stimulation (SCS) is an emerging, minimally invasive procedure used to treat patients with intractable chronic pain conditions. Although several signaling pathways have been proposed to account for SCS-mediated pain relief, the precise mechanisms remain poorly understood. Recent evidence reveals that injured sensory neuron-derived colony-stimulating factor 1 (CSF1) induces microglial activation in the spinal cord, contributing to the development of neuropathic pain (NP). Here, we tested the hypothesis that SCS relieves pain in a rat model of chronic constriction injury (CCI) by attenuating microglial activation via blocking CSF1 to the spinal cord. METHODS: Sprague-Dawley rats underwent sciatic nerve ligation to induce CCI and were implanted with an epidural SCS lead. SCS was delivered 6 hours per day for 5 days. Some rats received a once-daily intrathecal injection of CSF1 for 3 days during SCS. RESULTS: Compared with naive rats, CCI rats had a marked decrease in the mechanical withdrawal threshold of the paw, along with increased microglial activation and augmented CSF1 levels in the spinal dorsal horn and dorsal root ganglion, as measured by immunofluorescence or Western blotting. SCS significantly increased the mechanical withdrawal threshold and attenuated microglial activation in the spinal dorsal horn in CCI rats, which were associated with reductions in CSF1 levels in the spinal dorsal horn and dorsal roots but not dorsal root ganglion. Moreover, intrathecal injection of CSF1 completely abolished SCS-induced changes in the mechanical withdrawal threshold and activation of microglia in the spinal dorsal horn in CCI rats. CONCLUSIONS: SCS reduces microglial activation in the spinal cord and alleviates chronic NP, at least in part by inhibiting the release of CSF1 from the dorsal root ganglion ipsilateral to nerve injury.


Assuntos
Neuralgia , Estimulação da Medula Espinal , Animais , Constrição , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/terapia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Neuralgia/terapia , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/metabolismo
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