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1.
Int J Sports Phys Ther ; 14(6): 845-859, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31803517

RESUMO

BACKGROUND: Knowledge of the body's response to and recovery from exercise is rapidly increasing. State-of-the-art equipment and facilities allow recreationally active adults to seek innovations to enhance performance and shorten recovery time. Myofascial rolling (MR) is a relatively new practice, providing acute benefits for muscle pain and range of motion (ROM). However, there is no consensus on optimal MR duration. PURPOSE: The purpose of this systematic review is to determine the optimal MR duration using a foam roller or a roller massager for muscle pain, ROM, and athletic performance via qualitative review. STUDY DESIGN: Systematic Review of the Literature. METHODS: A systematic search was conducted using PubMed, EMBASE, EBSCOHost and PEDro (July 2018). Twenty-two studies met the inclusion criteria and were appraised using the PEDro scale. Studies were grouped by outcome measure, with a total number of subjects of n = 328 for pain/soreness, n = 398 for ROM, and n = 241 for performance. Heterogeneity of data prohibited a formal meta-analysis: studies were manually reviewed and classified as providing evidence for benefit of MR (i.e., significant positive effect) or not (i.e., null or negative effect) for each of the studied outcomes. RESULTS: The most evidence-based benefit of MR is the alleviation of muscle soreness; seven of eight studies assessing pain/soreness resulted in a short-term reduction, and a minimum dose of 90 seconds per muscle appeared beneficial. While ten of 17 studies involving ROM showed acute improvements, the results were inconsistent and highly variable. No significant effects on performance were detected. CONCLUSION: Available data indicate that MR for 90 seconds per muscle group may be the minimal duration to achieve a short-term reduction in pain/soreness, with no upper limit found. Results do not support increases in chronic ROM or performance, and data are insufficient to provide a conclusive recommendation for impacting acute ROM. The heterogeneity of the literature highlights the need for additional research to determine optimal dose of MR. LEVEL OF EVIDENCE: 2a- (Systematic Review with heterogeneity).

2.
eNeuro ; 6(2)2019.
Artigo em Inglês | MEDLINE | ID: mdl-30993183

RESUMO

Genome editing techniques have facilitated significant advances in our understanding of fundamental biological processes, and the Cre-Lox system has been instrumental in these achievements. Driving Cre expression specifically in injured neurons has not been previously possible: we sought to address this limitation in mice using a Cre-ERT2 construct driven by a reliable indicator of axotomy, activating transcription factor 3 (ATF3). When crossed with reporter mice, a significant amount of recombination was achieved (without tamoxifen treatment) in peripherally-projecting sensory, sympathetic, and motoneurons after peripheral nerve crush in hemizygotes (65-80% by 16 d) and was absent in uninjured neurons. Importantly, injury-induced recombination did not occur in Schwann cells distal to the injury, and with a knock-out-validated antibody we verified an absence of ATF3 expression. Functional recovery following sciatic nerve crush in ATF3-deficient mice (both hemizygotes and homozygotes) was delayed, indicating previously unreported haploinsufficiency. In a proof-of-principle experiment, we crossed the ATF3-CreERT2 line with a floxed phosphatase and tensin homolog (PTEN) line and show significantly improved axonal regeneration, as well as more complete recovery of neuromuscular function. We also demonstrate the utility of the ATF3-CreERT2 hemizygous line by characterizing recombination after lateral spinal hemisection (C8/T1), which identified specific populations of ascending spinal cord neurons (including putative spinothalamic and spinocerebellar) and descending supraspinal neurons (rubrospinal, vestibulospinal, reticulospinal and hypothalamic). We anticipate these mice will be valuable in distinguishing axotomized from uninjured neurons of several different classes (e.g., via reporter expression), and in probing the function of any number of genes as they relate to neuronal injury and regeneration.


Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Edição de Genes/métodos , Regulação da Expressão Gênica , Regeneração Nervosa , Traumatismos dos Nervos Periféricos , Recuperação de Função Fisiológica , Células de Schwann , Células Receptoras Sensoriais , Traumatismos da Medula Espinal , Fator 3 Ativador da Transcrição/deficiência , Animais , Axotomia , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Estudos de Viabilidade , Expressão Gênica/genética , Integrases/metabolismo , Camundongos , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/metabolismo , Estudo de Prova de Conceito , Células de Schwann/metabolismo , Nervo Isquiático/lesões , Células Receptoras Sensoriais/metabolismo
3.
J Neurosci ; 37(36): 8635-8654, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28760862

RESUMO

Spontaneous remyelination occurs after spinal cord injury (SCI), but the extent of myelin repair and identity of the cells responsible remain incompletely understood and contentious. We assessed the cellular origin of new myelin by fate mapping platelet-derived growth factor receptor α (PDGFRα), Olig2+, and P0+ cells following contusion SCI in mice. Oligodendrocyte precursor cells (OPCs; PDGFRα+) produced oligodendrocytes responsible for de novo ensheathment of ∼30% of myelinated spinal axons at injury epicenter 3 months after SCI, demonstrating that these resident cells are a major contributor to oligodendrocyte regeneration. OPCs also produced the majority of myelinating Schwann cells in the injured spinal cord; invasion of peripheral myelinating (P0+) Schwann cells made only a limited contribution. These findings reveal that PDGFRα+ cells perform diverse roles in CNS repair, as multipotential progenitors that generate both classes of myelinating cells. This endogenous repair might be exploited as a therapeutic target for CNS trauma and disease.SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to profound functional deficits, though substantial numbers of axons often survive. One possible explanation for these deficits is loss of myelin, creating conduction block at the site of injury. SCI leads to oligodendrocyte death and demyelination, and clinical trials have tested glial transplants to promote myelin repair. However, the degree and duration of myelin loss, and the extent and mechanisms of endogenous repair, have been contentious issues. Here, we use genetic fate mapping to demonstrate that spontaneous myelin repair by endogenous oligodendrocyte precursors is much more robust than previously recognized. These findings are relevant to many types of CNS pathology, raising the possibility that CNS precursors could be manipulated to repair myelin in lieu of glial transplantation.


Assuntos
Bainha de Mielina/patologia , Regeneração Nervosa/fisiologia , Células-Tronco Neurais/patologia , Plasticidade Neuronal , Oligodendroglia/fisiologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Diferenciação Celular , Proliferação de Células , Feminino , Masculino , Camundongos
4.
Acta Neuropathol Commun ; 3: 74, 2015 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-26610346

RESUMO

BACKGROUND: Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently. RESULTS: We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor. CONCLUSIONS: This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.


Assuntos
Colesterol/metabolismo , Sistema Nervoso/citologia , Neurônios/fisiologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , Regulação para Cima/efeitos dos fármacos , Fator 3 Ativador da Transcrição/genética , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Relação Dose-Resposta a Droga , Epóxido Hidrolases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Lectinas de Plantas/genética , Lectinas de Plantas/metabolismo , Óleos de Plantas/farmacologia , Regiões Promotoras Genéticas , Vitamina E/farmacologia
6.
Lancet Neurol ; 13(12): 1241-56, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25453463

RESUMO

Spinal cord injury is currently incurable and treatment is limited to minimising secondary complications and maximising residual function by rehabilitation. Improved understanding of the pathophysiology of spinal cord injury and the factors that prevent nerve and tissue repair has fuelled a move towards more ambitious experimental treatments aimed at promoting neuroprotection, axonal regeneration, and neuroplasticity. By necessity, these new options are more invasive. However, in view of recent advances in spinal cord injury research and demand from patients, clinicians, and the scientific community to push promising experimental treatments to the clinic, momentum and optimism exist for the translation of candidate experimental treatments to clinical spinal cord injury. The ability to rescue, reactivate, and rewire spinal systems to restore function after spinal cord injury might soon be within reach.


Assuntos
Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Animais , Descompressão Cirúrgica/métodos , Células-Tronco Embrionárias/transplante , Humanos , Plasticidade Neuronal/fisiologia , Traumatismos da Medula Espinal/diagnóstico
7.
Front Physiol ; 3: 257, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22934013

RESUMO

Spinal cord injury (SCI) triggers profound changes in visceral and somatic targets of sensory neurons below the level of injury. Despite this, little is known about the influence of injury to the spinal cord on sensory ganglia. One of the defining characteristics of sensory neurons is the size of their cell body: for example, nociceptors are smaller in size than mechanoreceptors or proprioceptors. In these experiments, we first used a comprehensive immunohistochemical approach to characterize the size distribution of sensory neurons after high- and low-thoracic SCI. Male Wistar rats (300 g) received a spinal cord transection (T3 or T10) or sham-injury. At 30 days post-injury, dorsal root ganglia (DRGs) and spinal cords were harvested and analyzed immunohistochemically. In a wide survey of primary afferents, only those expressing the capsaicin receptor (TRPV1) exhibited somal hypertrophy after T3 SCI. Hypertrophy only occurred caudal to SCI and was pronounced in ganglia far distal to SCI (i.e., in L4-S1 DRGs). Injury-induced hypertrophy was accompanied by a small expansion of central territory in the lumbar spinal dorsal horn and by evidence of TRPV1 upregulation. Importantly, hypertrophy of TRPV1-positive neurons was modest after T10 SCI. Given the specific effects of T3 SCI on TRPV1-positive afferents, we hypothesized that these afferents contribute to autonomic dysreflexia (AD). Rats with T3 SCI received vehicle or capsaicin via intrathecal injection at 2 or 28 days post-SCI; at 30 days, AD was assessed by recording intra-arterial blood pressure during colo-rectal distension (CRD). In both groups of capsaicin-treated animals, the severity of AD was dramatically reduced. While AD is multi-factorial in origin, TRPV1-positive afferents are clearly involved in AD elicited by CRD. These findings implicate TRPV1-positive afferents in the initiation of AD and suggest that TRPV1 may be a therapeutic target for amelioration or prevention of AD after high SCI.

8.
J Neurotrauma ; 29(8): 1638-49, 2012 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-22260380

RESUMO

The severity of injury to cardiovascular autonomic pathways following clinical spinal cord injury (SCI) can be evaluated with spectral analyses. Whether this technique provides a translatable assessment of cardiovascular autonomic function in rodent SCI is unknown. Beat-to-beat blood pressure and pulse interval were measured in male rats 1 month after complete T3 or T10 SCI, and in uninjured control animals. Univariate autoregressive spectral analyses were performed and the power of the low frequency (LF), high frequency (HF), and very low frequency (VLF) peaks identified. Frequency domain variables were correlated with the severity of orthostatic hypotension (OH) and the severity of hypertension during autonomic dysreflexia (AD). Total heart rate variability (HRV) and blood pressure variability (BPV) were reduced in animals with T3, but not T10, SCI. VLF and LF HRV were reduced and HF HRV was increased in animals with T3 SCI compared to controls; there were no changes in animals with T10 SCI. BPV in the VLF and LF range was reduced in animals with T3 SCI, but not T10 SCI. In all animals with SCI, severity of OH was positively correlated with LF BPV, and negatively correlated with HF BPV. Severity of AD was positively correlated with HF BPV and HF HRV, and negatively correlated with VLF HRV. Spectral analyses can detect alterations in cardiovascular autonomic function in animals with SCI at rest. These parameters underscore the distinct cardiovascular ramifications of high- versus low-thoracic SCI, and correlate with the severity of AD and OH, clinically-relevant measures of abnormal blood pressure control.


Assuntos
Vias Autônomas/fisiopatologia , Pressão Sanguínea/fisiologia , Sistema Cardiovascular/fisiopatologia , Frequência Cardíaca/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Disreflexia Autonômica/fisiopatologia , Hipotensão Ortostática/fisiopatologia , Masculino , Ratos , Ratos Wistar
9.
Spine J ; 10(12): 1108-17, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21094471

RESUMO

BACKGROUND CONTEXT: Individuals with high spinal cord injury (SCI) are prone to significant fluctuation in blood pressure with episodes of very high and low blood pressure during autonomic dysreflexia (AD) and orthostatic hypotension, respectively. We do not know how such blood pressure lability affects the vasculature. PURPOSE: We used a well-characterized animal model of AD to determine whether increasing the frequency of AD during recovery from SCI would exacerbate injury-induced dysfunction in resistance vessels. STUDY DESIGN/SETTING: Experimental animal study. International Collaboration On Repair Discoveries (ICORD), University of British Columbia, Canada. METHODS: Complete transection of the T3 spinal cord was performed in male Wistar rats. For 14 days after injury, AD was induced via colorectal distension (CRD; 30 minutes per day) in the experimental group (SCI-CRD). One month after SCI, baseline cardiovascular parameters and severity of CRD-induced AD were assessed in SCI-CRD animals and SCI-only controls. Mesenteric arteries were harvested for in vitro myography to characterize vasoactive responses to phenylephrine (PE) and acetylcholine (ACh). RESULTS: Mesenteric arteries from SCI-CRD animals exhibited larger maximal responses to PE than arteries from SCI-only controls. Hyperresponsiveness to PE was not a product of endothelial dysfunction because mesenteric arteries from both groups had similar vasodilator responses to ACh. Both SCI-only controls and SCI-CRD animals exhibited CRD-evoked AD 1 month after SCI; however, CRD-induced hypertension was less pronounced in animals that were previously exposed to CRD. CONCLUSIONS: Injury-induced changes within the vasculature may contribute to the development of AD after SCI. Here, we provide evidence that AD itself has significant and long-lasting effects on vascular function. This finding has implications for the medical management of AD and provides an impetus for maintaining stable blood pressure.


Assuntos
Disreflexia Autonômica/complicações , Endotélio Vascular/fisiopatologia , Traumatismos da Medula Espinal/complicações , Doenças Vasculares/etiologia , Acetilcolina/farmacologia , Análise de Variância , Animais , Disreflexia Autonômica/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Miografia , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/fisiopatologia , Vértebras Torácicas , Doenças Vasculares/fisiopatologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
10.
J Neurotrauma ; 27(9): 1709-22, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20597687

RESUMO

The complications of spinal cord injury (SCI) increase in number and severity with the level of injury. A recent survey of SCI researchers reveals that animal models of high SCI are essential. Despite this consensus, most laboratories continue to work with mid- or low-thoracic SCI. The available data on cervical SCI in animals characterize incomplete injuries; for example, nearly all studies published in 2009 examine discrete, tract-specific lesions that are not clinically-relevant. A primary barrier to developing animal models of severe, higher SCI is the challenge of animal care, a critical determinant of experimental outcome. Currently, many of these practices vary substantially between laboratories, and are passed down anecdotally within institutions. The care of animals with SCI is complex, and becomes much more challenging as the lesion level ascends. In our experience, the care of animals with high-thoracic (T3) SCI is much more demanding than the care of animals with low-thoracic SCI, even though both injuries result in paraplegia. We have developed an animal care regimen for rats with complete high-thoracic SCI. Our practices have been refined over the past 7 years, in collaboration with animal care centre staff and veterinarians. During this time, we have cared for more than 300 rats with T3 complete transection SCI, with experimental end-points of up to 3 months. Here we provide details of our animal care procedures, including acclimatization, housing, diet, antibiotic prophylaxis, surgical procedures, post-operative monitoring, and prevention of complications. In our laboratory, this comprehensive approach consistently produces good outcomes following T3 complete transection SCI: using body weight as an objective indicator of animal health, we have found that our rats typically return to pre-operative weights within 10 days of T3 complete SCI. It is our hope that the information provided here will improve care of experimental animals, and facilitate adoption of models that directly address the complications associated with higher level injuries.


Assuntos
Bem-Estar do Animal , Modelos Animais de Doenças , Abrigo para Animais , Ciência dos Animais de Laboratório/métodos , Traumatismos da Medula Espinal/terapia , Bem-Estar do Animal/normas , Animais , Abrigo para Animais/normas , Masculino , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/terapia , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/reabilitação , Vértebras Torácicas
11.
PLoS One ; 5(12): e15821, 2010 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-21209910

RESUMO

To improve science learning, science educators' teaching tools need to address two major criteria: teaching practice should mirror our current understanding of the learning process; and science teaching should reflect scientific practice. We designed a small-group learning (SGL) model for a fourth year university neurobiology course using these criteria and studied student achievement and attitude in five course sections encompassing the transition from individual work-based to SGL course design. All students completed daily quizzes/assignments involving analysis of scientific data and the development of scientific models. Students in individual work-based (Individualistic) sections usually worked independently on these assignments, whereas SGL students completed assignments in permanent groups of six. SGL students had significantly higher final exam grades than Individualistic students. The transition to the SGL model was marked by a notable increase in 10th percentile exam grade (Individualistic: 47.5%; Initial SGL: 60%; Refined SGL: 65%), suggesting SGL enhanced achievement among the least prepared students. We also studied student achievement on paired quizzes: quizzes were first completed individually and submitted, and then completed as a group and submitted. The group quiz grade was higher than the individual quiz grade of the highest achiever in each group over the term. All students--even term high achievers--could benefit from the SGL environment. Additionally, entrance and exit surveys demonstrated student attitudes toward SGL were more positive at the end of the Refined SGL course. We assert that SGL is uniquely-positioned to promote effective learning in the science classroom.


Assuntos
Biologia/educação , Educação de Graduação em Medicina/métodos , Aprendizagem , Ensino/métodos , Atitude , Cognição , Currículo , Feminino , Objetivos , Humanos , Masculino , Estudantes
12.
Pain ; 138(1): 98-110, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18158214

RESUMO

Brain-derived neurotrophic factor (BDNF) has multiple effects on tropomyosin-related receptor kinase B--(TrkB) expressing neurons, including potentiation of spinal nociceptive transmission and stimulation of axon outgrowth. BDNF is upregulated in the spinal cord following dorsal root injury (DRI), a manipulation which elicits both pain and collateral sprouting. Transection of the C7 and C8 dorsal roots (C7/8 DRI) generates cold pain in the ipsilateral forepaw which peaks at 10 days, and resolves within three weeks after injury. In the present study, we investigated the influence of chronic BDNF sequestration, by intrathecal delivery of TrkB-Fc, on the plasticity of nociceptive circuitry and resultant cold pain behaviour following spinal deafferentation. C7/8 DRI resulted in a pronounced deafferentation of the C7 dorsal horn and significant depletion of both peptidergic- and non-peptidergic nociceptive projections. While changes in GAP-43 expression revealed that endogenous BDNF was exerting an overall plasticity-promoting influence on intraspinal axons after DRI, continuous TrkB-Fc treatment stimulated sprouting of nociceptive terminals. DRI stimulated a BDNF-dependent increase in the density of GABAergic interneuronal processes, as indicated by increased vesicular GABA transporter--(VGAT) and neuropeptide Y--(NPY) positive terminal densities. Finally, chronic TrkB-Fc treatment prevented cold pain resolution. These findings demonstrate that endogenous BDNF has both plasticity-promoting and plasticity-suppressing effects on the intrinsic spinal components of nociceptive circuitry, which are likely to underlie cold pain behaviour following C7/8 DRI.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Gânglios Espinais/fisiopatologia , Gânglios Espinais/cirurgia , Hiperalgesia/fisiopatologia , Plasticidade Neuronal , Rizotomia , Animais , Temperatura Baixa , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica
14.
J Neurosci ; 27(21): 5812-22, 2007 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-17522325

RESUMO

Dorsal root injury (DRI) disrupts the flow of sensory information to the spinal cord. Although primary afferents do not regenerate to their original targets, spontaneous recovery can, by unknown mechanisms, occur after DRI. Here, we show that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not nerve growth factor or neurotrophin-4, are upregulated in the spinal gray matter after DRI. Because endogenous BDNF and NT-3 have well established roles in synaptic and axonal plasticity, we hypothesized that they contributed to spontaneous recovery after DRI. We first developed a model of DRI-induced mechanosensory dysfunction: rat C7/8 DRI produced a deficit in low-threshold cutaneous mechanosensation that spontaneously improved within 10 d but did not recover completely. To determine the effects of endogenous BDNF and NT-3, we administered TrkB-Fc or TrkC-Fc fusion proteins throughout the recovery period. To our surprise, TrkB-Fc stimulated complete recovery of mechanosensation by 6 d after DRI. It also stimulated mechanosensory axon sprouting but prevented deafferentation-induced serotonergic sprouting. TrkC-Fc had no effect on low-threshold mechanosensory behavior or axonal plasticity. There was no mechanosensory improvement with single-bolus TrkB-Fc infusions at 10 d after DRI (despite significantly reducing rhizotomy-induced cold pain), indicating that neuromodulatory effects of BDNF did not underlie mechanosensory recovery. Continuous infusion of the pan-neurotrophin antagonist K252a also stimulated behavioral and anatomical plasticity, indicating that these effects of TrkB-Fc treatment occurred independent of signaling by other neurotrophins. These results illustrate a novel, plasticity-suppressing effect of endogenous TrkB ligands on mechanosensation and mechanosensory primary afferent axons after spinal deafferentation.


Assuntos
Mecanotransdução Celular/fisiologia , Plasticidade Neuronal/fisiologia , Receptor trkB/fisiologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Animais , Ligantes , Masculino , Mecanotransdução Celular/efeitos dos fármacos , Fatores de Crescimento Neural/biossíntese , Fatores de Crescimento Neural/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor trkB/agonistas
15.
Mol Neurobiol ; 33(2): 91-111, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16603791

RESUMO

Functional re-innervation of target neurons following neurological damage such as spinal cord injury is an essential requirement of potential therapies. There are at least two avenues by which this can be achieved: (a) through the regeneration of injured axons and (b) through promoting plasticity of those spared by the initial insult. There are several reasons why the latter approach may be more feasible, not the least of which are the inhibitory character of the glial scar, the often long distances over which injured axons must regrow, and the fact that spared axons are often already in the vicinity of denervated targets. The challenge is to unveil the well-recognized intrinsic plasticity of spared axons in a way that avoids complications, such as pain or autonomic dysfunction. One approach that we as well as others have taken is to target growth-suppressing signaling pathways initiated in spared axons by myelin-derived proteins. This article reviews models used for the study of spinal axon plasticity and describes the anatomical and behavioral effects of interfering with myelinderived proteins, their receptors, and components of their intracellular signaling cascades.


Assuntos
Cones de Crescimento/metabolismo , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Cones de Crescimento/efeitos dos fármacos , Inibidores do Crescimento/antagonistas & inibidores , Inibidores do Crescimento/metabolismo , Humanos , Proteínas da Mielina/antagonistas & inibidores , Proteínas da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Traumatismos da Medula Espinal/fisiopatologia
16.
J Neurosci ; 24(48): 10796-805, 2004 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-15574730

RESUMO

Dorsal rhizotomy results in primary deafferentation of the dorsal horn with concomitant sprouting of spared intraspinal monoaminergic axons. Because descending monoaminergic systems are thought to mitigate nociceptive transmission from the periphery and because dorsal rhizotomy can result in neuropathic pain, we sought to determine whether the rhizotomy-induced sprouting response could be further augmented. Because myelin-derived molecules mask endogenous plasticity of CNS axons and because myelin-inhibitory signaling occurs through the Rho-GTPase pathway, we inhibited Rho-pathway signaling after cervical dorsal rhizotomy in rats. An increase in the density of serotonergic- and tyrosine hydroxylase-positive fibers was seen in the dorsal horn 1 week after septuple rhizotomy, and axon density continued to increase for at least 1 month. One week after septuple rhizotomy, administration of intrathecal Y-27632, an antagonist of Rho-kinase (ROCK), increased the density of both fiber types over vehicle-treated controls. To examine behavioral effects of both cervical rhizotomy and ROCK inhibition, we examined responses to evoked pain: mechanical and thermal allodynia and cold hyperalgesia in the forepaw were examined after single, double, and quadruple rhizotomies of dorsal roots of the brachial plexus. The most notable behavioral outcome was the development of cold hyperalgesia in the affected forepaw after rhizotomies of the C7 and C8 dorsal roots. Application of Y-27632 both attenuated cold hyperalgesia and induced monoaminergic plasticity after C7/8 rhizotomy. Thus, inhibition of Rho-pathway signaling both promoted the sprouting of intact supraspinal monoaminergic fibers and alleviated pain after dorsal rhizotomy.


Assuntos
Amidas/farmacologia , Causalgia/enzimologia , Hiperalgesia/tratamento farmacológico , Proteínas do Tecido Nervoso/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Células do Corno Posterior/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Piridinas/farmacologia , Rizotomia , Amidas/administração & dosagem , Amidas/uso terapêutico , Animais , Axônios/patologia , Biomarcadores , Plexo Braquial/fisiopatologia , Causalgia/tratamento farmacológico , Causalgia/patologia , Temperatura Baixa/efeitos adversos , Dopamina/fisiologia , Membro Anterior/inervação , Temperatura Alta/efeitos adversos , Hiperalgesia/enzimologia , Hiperalgesia/etiologia , Injeções Espinhais , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Fibras Nervosas/química , Fibras Nervosas/patologia , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/antagonistas & inibidores , Medição da Dor , Proteína Quinase C/análise , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Ratos , Ratos Wistar , Serotonina/fisiologia , Transdução de Sinais , Método Simples-Cego , Estresse Mecânico , Tirosina 3-Mono-Oxigenase/análise , Quinases Associadas a rho
17.
Glia ; 47(2): 189-206, 2004 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-15185397

RESUMO

Olfactory ensheathing cells (OECs) may support axonal regrowth, and thus might be a viable treatment for spinal cord injury (SCI); however, peripherally-derived OECs remain untested in most animal models of SCI. We have transplanted OECs from the lamina propria (LP) of mice expressing green fluorescent protein (GFP) in all cell types into immunosuppressed rats with cervical or lumbar dorsal root injuries. LP-OECs were deposited into either the dorsal root ganglion (DRG), intact or injured dorsal roots, or the dorsal columns via the dorsal root entry zone (DREZ). LP-OECs injected into the DRG or dorsal root migrated centripetally, and migration was more extensive in the injured root than in the intact root. These peripherally deposited OECs migrated within the PNS but did not cross the DREZ; similarly, large- or small-caliber primary afferents were not seen to regenerate across the DREZ. LP-OEC deposition into the dorsal columns via the DREZ resulted in a laminin-rich injection track: due to the pipette trajectory, this track pierced the glia limitans at the DREZ. OECs migrated centrifugally through this track, but did not traverse the DREZ; axons entered the spinal cord via this track, but were not seen to reenter CNS tissue. We found a preferential association between CGRP-positive small- to medium-diameter afferents and OEC deposits in injured dorsal roots as well as within the spinal cord. In the cord, OEC deposition resulted in increased angiogenesis and altered astrocyte alignment. These data are the first to demonstrate interactions between sensory axons and peripherally-derived OECs following dorsal root injury.


Assuntos
Vias Aferentes/crescimento & desenvolvimento , Regeneração Nervosa , Neuroglia/transplante , Mucosa Olfatória/transplante , Radiculopatia/terapia , Raízes Nervosas Espinhais/lesões , Vias Aferentes/lesões , Vias Aferentes/patologia , Animais , Astrócitos/citologia , Astrócitos/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Movimento Celular/fisiologia , Tamanho Celular/fisiologia , Células Cultivadas , Denervação , Modelos Animais de Doenças , Gânglios Espinais/crescimento & desenvolvimento , Gânglios Espinais/patologia , Gânglios Espinais/cirurgia , Proteínas de Fluorescência Verde , Cones de Crescimento/fisiologia , Cones de Crescimento/ultraestrutura , Laminina/metabolismo , Proteínas Luminescentes , Masculino , Camundongos , Camundongos Transgênicos , Neovascularização Fisiológica/fisiologia , Neuroglia/citologia , Mucosa Olfatória/citologia , Mucosa Olfatória/crescimento & desenvolvimento , Radiculopatia/patologia , Ratos , Ratos Wistar , Rizotomia , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/patologia , Medula Espinal/cirurgia , Raízes Nervosas Espinhais/crescimento & desenvolvimento , Raízes Nervosas Espinhais/patologia , Transplante de Tecidos/métodos , Transplante Heterólogo , Falha de Tratamento
18.
J Comp Neurol ; 473(1): 1-15, 2004 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-15067714

RESUMO

Bridging of a lesion site and minimizing local damage to create an environment permissive for regeneration are both primary components of a successful strategy to repair spinal cord injury (SCI). Olfactory ensheathing cells (OECs) are prime candidates for autologous transplantation to bridge this gap, but little is known currently about their mechanism of action. In addition, OECs from the accessible lamina propria (LP) of the olfactory mucosa are a more viable source in humans but have yet to be tested for their ability to promote regeneration in established SCI models. Here, mouse LP-OECs expressing green fluorescent protein (GFP) transplanted directly into both rat and mouse dorsolateral spinal cord lesion sites demonstrate limited migration but interact with host astrocytes to develop a new transitional zone at the lesion border. LP-OECs also promote extensive migration of host Schwann cells into the central nervous system repair zone and stimulate angiogenesis to provide a biological scaffold for repair. This novel environment created by transplanted and host glia within the spinal cord inhibits cavity and scar formation and promotes extensive sprouting of multiple sensory and motor axons into and through the lesion site. Sixty days after rat SCI, serotonin- and tyrosine hydroxylase-positive axons sprouted across the lesion into the distal cord, although axotomized rubrospinal axons did not. Thus, even in a xenotransplant paradigm, LP-OECs work collaboratively with host glial cells to create an environment to ameliorate local damage and simultaneously promote a regenerative response in multiple axonal populations.


Assuntos
Biotina/análogos & derivados , Neuroglia/fisiologia , Mucosa Olfatória/patologia , Regeneração/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Cicatrização/fisiologia , Animais , Animais Recém-Nascidos , Axônios/metabolismo , Axônios/transplante , Biotina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Dextranos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Fluorescência Verde , Imuno-Histoquímica/métodos , Proteínas Luminescentes/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas de Neurofilamentos/metabolismo , Neuroglia/transplante , Proteínas Oncogênicas v-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Traumatismos da Medula Espinal/patologia , Fatores de Tempo , Transplante Autólogo/métodos , Tubulina (Proteína)/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
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