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1.
Life Sci ; 243: 117308, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954163

RESUMO

Compromised functional regains in about half of the patients following surgical nerve repair pose a serious socioeconomic burden to the society. Although surgical strategies such as end-to-end neurorrhaphy, nerve grafting and nerve transfer are widely applied in distal injuries leading to optimal recovery; however in proximal nerve defects functional outcomes remain unsatisfactory. Biomedical engineering approaches unite the efforts of the surgeons, engineers and biologists to develop regeneration facilitating structures such as extracellular matrix based supportive polymers and tubular nerve guidance channels. Such polymeric structures provide neurotrophic support from injured nerve stumps, retard the fibrous tissue infiltration and guide regenerating axons to appropriate targets. The development and application of nerve guidance conduits (NGCs) to treat nerve gap injuries offer clinically relevant and feasible solutions. Enhanced understanding of the nerve regeneration processes and advances in NGCs design, polymers and fabrication strategies have led to developing modern NGCs with superior regeneration-conducive capacities. Current review focuses on the advances in surgical and engineering approaches to treat peripheral nerve injuries. We suggest the incorporation of endothelial cell growth promoting cues and factors into the NGC interior for its possible enhancement effects on the axonal regeneration process that may result in substantial functional outcomes.


Assuntos
Traumatismos dos Nervos Periféricos/terapia , Animais , Materiais Biocompatíveis , Humanos , Regeneração Nervosa/fisiologia
2.
Plast Reconstr Surg ; 145(2): 368e-381e, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31985643

RESUMO

BACKGROUND: Acellular nerve allografts are a viable treatment modality for bridging nerve gaps. Several small studies have demonstrated results equal to those of autologous grafts; however, there is information lacking with regard to outcomes for wider indications. The authors evaluated the outcomes of patients treated with a nerve allograft in a variety of clinical situations. METHODS: A retrospective chart analysis was completed between April of 2009 and October of 2017. Inclusion criteria were age 18 years or older at the time of surgery and treatment with a nerve allograft. Patients were excluded if they had not been followed up for a minimum of 6 months. The modified Medical Research Council Classification was used to monitor motor and sensory changes in the postoperative period. RESULTS: Two hundred seven nerve allografts were used in 156 patients; of these, 129 patients with 171 nerve allografts fulfilled the inclusion criteria. Seventy-seven percent of patients achieved a sensory outcome score of S3 or above and 36 percent achieved a motor score of M3 or above. All patients with chronic pain had improvement of their symptoms. Graft length and diameter were negatively correlated with reported outcomes. One patient elected to undergo revision surgery, and the original graft was shown histologically to have extensive central necrosis. Anatomically, allografts used for lower limb reconstruction yielded the poorest results. All chronic patients had a significantly lower postoperative requirement for analgesia, and allografts were effective in not only reducing pain but also restoring a functional level of sensation. CONCLUSIONS: This study supports the wider application of allografts in managing nerve problems. However, caution must be applied to the use of long grafts with larger diameters. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.


Assuntos
Traumatismos dos Nervos Periféricos/cirurgia , Nervos Periféricos/transplante , Procedimentos Cirúrgicos Reconstrutivos/métodos , Adulto , Idoso , Aloenxertos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regeneração Nervosa/fisiologia , Neuralgia/cirurgia , Estudos Retrospectivos , Adulto Jovem
3.
Life Sci ; 241: 117102, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790691

RESUMO

Peripheral nerve injuries are common conditions that often lead to dysfunctions. Although much knowledge exists on the several factors that mediate the complex biological process involved in peripheral nerve regeneration, there is a lack of effective treatments that ensure full functional recovery. Naringenin (NA) is the most abundant flavanone found in citrus fruits and it has promising neuroprotective, anti-inflammatory and antioxidant effects. This study aimed to enhance peripheral nerve regeneration using an inclusion complex containing NA and hydroxypropyl-ß-cyclodextrin (HPßCD), named NA/HPßCD. A mouse sciatic nerve crush model was used to evaluate the effects of NA/HPßCD on nerve regeneration. Sensory and motor parameters, hyperalgesic behavior and the sciatic functional index (SFI), respectively, improved with NA treatment. Western blot analysis revealed that the levels of p75NTR ICD and p75NTR full length as well phospho-JNK/total JNK ratios were preserved by NA treatment. In addition, NA treatment was able to decrease levels of caspase 3. The concentrations of TNF-α and IL-1ß were decreased in the lumbar spine, on the other hand there was an increase in IL-10. NA/HPßCD presented a better overall morphological profile but it was not able to increase the number of myelinated fibers. Thus, NA was able to enhance nerve regeneration, and NA/HPßCD decreased effective drug doses while maintaining the effect of the pure drug, demonstrating the advantage of using the complex over the pure compound.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Flavanonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Nervo Isquiático/fisiologia , Animais , Hiperalgesia/tratamento farmacológico , Interleucina-10/metabolismo , Masculino , Camundongos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Medição da Dor , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/metabolismo , Recuperação de Função Fisiológica , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Adv Clin Exp Med ; 28(12): 1717-1722, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31851789

RESUMO

Structural and functional synapse reorganization is one of the key issues of learning and memory mechanisms. Specific proteases, called matrix metalloproteinases (MMPs), play a pivotal role during learning-related modification of neural circuits. Different types of MMPs modify the extracellular perisynaptic environment, leading to the plastic changes in the synapses. In recent years, there has been an increasing interest in the role played by matrix metalloproteinase-3 (MMP-3) in various processes occurring in the mammalian brain, both in physiological and pathological conditions. In this review, we discuss a crucial function of MMP-3 in synaptic plasticity, learning, neuronal development, as well as in neuroregeneration. We discuss the involvement of MMP-3 in synaptic long-term potentiation, which is likely to have a profound impact on experience-dependent learning. On the other hand, we also provide examples of deleterious actions of uncontrolled MMP-3 activity on the central nervous system (CNS) and its contribution to Alzheimer's and Parkinson's diseases (AD and PD). Since the molecular mechanisms controlled by MMP-3 have a profound and diverse impact on physiological and pathological brain functioning, their deep understanding may be crucial for the development of more specific methods for the treatment of neuropsychiatric diseases.


Assuntos
Doenças do Sistema Nervoso Central/enzimologia , Metaloproteinase 3 da Matriz/fisiologia , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Humanos , Potenciação de Longa Duração , Potenciais Sinápticos/fisiologia
5.
Nat Rev Neurol ; 15(12): 732-745, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31728042

RESUMO

Over the past decade, we have witnessed a flourishing of novel strategies to enhance neuroplasticity and promote axon regeneration following spinal cord injury, and results from preclinical studies suggest that some of these strategies have the potential for clinical translation. Spinal cord injury leads to the disruption of neural circuitry and connectivity, resulting in permanent neurological disability. Recovery of function relies on augmenting neuroplasticity to potentiate sprouting and regeneration of spared and injured axons, to increase the strength of residual connections and to promote the formation of new connections and circuits. Neuroplasticity can be fostered by exploiting four main biological properties: neuronal intrinsic signalling, the neuronal extrinsic environment, the capacity to reconnect the severed spinal cord via neural stem cell grafts, and modulation of neuronal activity. In this Review, we discuss experimental evidence from rodents, nonhuman primates and patients regarding interventions that target each of these four properties. We then highlight the strengths and challenges of individual and combinatorial approaches with respect to clinical translation. We conclude by considering future developments and providing views on how to bridge the gap between preclinical studies and clinical translation.


Assuntos
Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/metabolismo , Pesquisa Médica Translacional/métodos , Animais , Axônios/fisiologia , Humanos , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/genética
6.
Nat Neurosci ; 22(11): 1913-1924, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591560

RESUMO

Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.


Assuntos
Axônios/fisiologia , Epigenômica , Gânglios Espinais/fisiologia , Regeneração Nervosa/fisiologia , Células Receptoras Sensoriais/fisiologia , Acetilação , Algoritmos , Animais , Fator de Ligação a CCCTC/genética , Cromatina/metabolismo , Feminino , Gânglios Espinais/lesões , Expressão Gênica , Histonas/metabolismo , Aprendizado de Máquina , Masculino , Camundongos , Camundongos Transgênicos , Nervo Isquiático/lesões , Análise de Sequência de RNA
7.
An Acad Bras Cienc ; 91(3): e20190068, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508664

RESUMO

To investigate the mechanism of different exercise patterns on neurological function after focal cerebral ischaemia in rats. Rats with focal cerebral cerebral ischaemia were randomly divided into an aerobic exercise group, an exhaustive exercise group and a control group, with 8 rats in each group. A score for nerve function in each group was calculated, and the ultrastructure of nerve cells was observed. Levels of NO and NOS in the brain motor area of the ​​rats were measured in each group. The aerobic exercise group had lower nerve function scores than the exhaustive exercise group and higher scores than the control group (P<0.05). Under transmission electron microscopy, irregular shapes and organs were observed in nerve cells in the control group, while regular cell shapes and organs were observed in the aerobic exercise group. The aerobic exercise group and exhaustive exercise group had higher measures of NO content, NOS activity and eNOS, nNOS and iNOS gene expression than the control group, but eNOS expression in the aerobic exercise group and iNOS expression in the exhaustive exercise group were clearly higher according to RT-PCR (P<0.05). Aerobic exercise can promote the expression of NOS, mainly in eNOS, which can promote nerve repair.


Assuntos
Isquemia Encefálica/fisiopatologia , Regeneração Nervosa/fisiologia , Óxido Nítrico/fisiologia , Condicionamento Físico Animal/métodos , Animais , Isquemia Encefálica/terapia , Modelos Animais de Doenças , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Sprague-Dawley
8.
Muscle Nerve ; 60(5): 629-636, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31397919

RESUMO

INTRODUCTION: Neuroenhancing therapies are desired because repair of nerve injuries can fail to achieve recovery. We compared two neuroenhancing therapies, electrical stimulation (ES) and systemic tacrolimus (FK506), for their capabilities to enhance regeneration in the context of a rat model. METHODS: Rats were randomized to four groups: ES 0.5 mA, ES 2.0 mA, FK506, and repair alone. All groups underwent tibial nerve transection and repair, and outcomes were assessed by using twice per week walking track analysis, cold allodynia response, relative muscle mass, and nerve histology. RESULTS: Electrical stimulation and FK506 groups demonstrated improved functional recovery and myelinated axon counts distal to the repair compared with repair alone. Electrical stimulation provided improvements in nerve regeneration that were not different from optimized FK506 systemic administration. DISCUSSION: Providing ES after nerve repair improved regeneration and recovery in rats, with minimal differences in therapeutic efficacy to FK506, further demonstrating its clinical potential to improve management of nerve injuries.


Assuntos
Estimulação Elétrica/métodos , Imunossupressores/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Tacrolimo/farmacologia , Nervo Tibial/lesões , Animais , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Regeneração Nervosa/fisiologia , Procedimentos Neurocirúrgicos , Traumatismos dos Nervos Periféricos , Ratos , Recuperação de Função Fisiológica/fisiologia , Nervo Tibial/patologia , Nervo Tibial/cirurgia
9.
Plast Reconstr Surg ; 144(5): 1105-1114, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31441804

RESUMO

BACKGROUND: Loss of elbow flexion commonly occurs following acute brachial plexus injury. The double fascicular transfer is often used in acute C5-C6 and C5-C7 root injuries, but is rarely applied in cases involving concomitant C8 or T1 root injury. The authors designed a rat model using varying severities of lower trunk injury to determine whether partial injury to the lower trunk affects nerve transfers for elbow flexion. METHODS: There were four different rat groups in which 0, 25, 75, or 100 percent of the donor lower trunk remained intact. One-fourth of the cross-sectional area of the ulnar nerve was then transferred to the musculocutaneous nerve immediately. The authors assessed outcomes using a grooming test, muscle mass, retrograde labeling of sensory/motor neurons that regenerated axons, and immunohistochemical stain of regenerated axons. RESULTS: Five months after nerve transfer, rats that underwent partial injury of the lower trunk fared significantly worse than the rats in whom the donor lower trunk remained 100 percent intact, but significantly better than the rats with 0 percent intact lower trunk. Rats with 25 or 75 percent of the lower trunk intact recovered equivalent function, at both the donor and recipient sites. CONCLUSIONS: Although relatively weak compared with the 100 percent intact donor lower trunk group, the partially injured donor nerve was still functional; even though the nerve sustained a partial injury, the residual axons reinnervated the target muscles. The power of the muscles following either 25 percent or 75 percent injuries was equal after the recovery. Resorting to this approach may be useful in cases in which no alternatives are available.


Assuntos
Neuropatias do Plexo Braquial/cirurgia , Plexo Braquial/lesões , Articulação do Cotovelo/inervação , Regeneração Nervosa/fisiologia , Transferência de Nervo/métodos , Doença Aguda , Animais , Plexo Braquial/cirurgia , Modelos Animais de Doenças , Articulação do Cotovelo/fisiologia , Seguimentos , Masculino , Distribuição Aleatória , Amplitude de Movimento Articular/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Estatísticas não Paramétricas , Resultado do Tratamento
10.
Exp Neurol ; 321: 113037, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31425689

RESUMO

Avulsion of spinal nerve roots is a severe proximal peripheral nerve lesion. Despite neurosurgical repair, recovery of function in human patients is disappointing, because spinal motor neurons degenerate progressively, axons grow slowly and the distal Schwann cells which are instrumental to supporting axon extension lose their pro-regenerative properties. We have recently shown that timed GDNF gene therapy (dox-i-GDNF) in a lumbar plexus injury model promotes axon regeneration and improves electrophysiological recovery but fails to stimulate voluntary hind paw function. Here we report that dox-i-GDNF treatment following avulsion and re-implantation of cervical ventral roots leads to sustained motoneuron survival and recovery of voluntary function. These improvements were associated with a twofold increase in motor axon regeneration and enhanced reinnervation of the hand musculature. In this cervical model the distal hand muscles are located 6,5 cm from the reimplantation site, whereas following a lumber lesion this distance is twice as long. Since the first signs of muscle reinnervation are observed 6 weeks after the lesion, this suggests that regenerating axons reached the hand musculature before a critical state of chronic denervation has developed. These results demonstrate that the beneficial effects of timed GDNF-gene therapy are more robust following spinal nerve avulsion lesions that allow reinnervation of target muscles within a relatively short time window after the lesion. This study is an important step in demonstrating the potential of timed GDNF-gene therapy to enhance axon regeneration after neurosurgical repair of a severe proximal nerve lesion.


Assuntos
Neuropatias do Plexo Braquial , Terapia Genética/métodos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Regeneração Nervosa/fisiologia , Recuperação de Função Fisiológica , Animais , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Radiculopatia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia
11.
Muscle Nerve ; 60(5): 604-612, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31408210

RESUMO

INTRODUCTION: In this study we present a reproducible technique to assess motor recovery after nerve injury via neuromuscular junction (NMJ) immunostaining and electrodiagnostic testing. METHODS: Wild-type mice underwent sciatic nerve transection with repair. Hindlimb muscles were collected for microscopy up to 30 weeks after injury. Immunostaining was used to assess axons (NF200), Schwann cells (S100), and motor endplates (α-bungarotoxin). Compound motor action potential (CMAP) amplitude was used to assess tibialis anterior (TA) function. RESULTS: One week after injury, nearly all (98.0%) endplates were denervated. At 8 weeks, endplates were either partially (28.3%) or fully (71.7%) reinnervated. At 16 weeks, NMJ reinnervation reached 87.3%. CMAP amplitude was 83% of naive mice at 16 weeks and correlated with percentage of fully reinnervated NMJs. Morphological differences were noted between injured and noninjured NMJs. DISCUSSION: We present a reproducible method for evaluating NMJ reinnervation. Electrodiagnostic data summarize NMJ recovery. Characterization of wild-type reinnervation provides important data for consideration in experimental design and interpretation.


Assuntos
Potenciais de Ação/fisiologia , Axônios/patologia , Músculo Esquelético/inervação , Regeneração Nervosa/fisiologia , Junção Neuromuscular/patologia , Células de Schwann/patologia , Animais , Bungarotoxinas , Camundongos , Placa Motora/patologia , Placa Motora/fisiopatologia , Denervação Muscular , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Proteínas de Neurofilamentos , Junção Neuromuscular/fisiopatologia , Procedimentos Neurocirúrgicos , Recuperação de Função Fisiológica , Proteínas S100 , Nervo Isquiático/lesões , Nervo Isquiático/cirurgia , Coloração e Rotulagem , Cicatrização
12.
Acta Otolaryngol ; 139(9): 823-827, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31268392

RESUMO

Background: The degree of distress caused by the sequelae of peripheral facial nerve palsy usually depends on the severity of synkinesis. Objective: To clarify whether electroneurography (ENoG) can predict the severity of synkinesis after peripheral facial nerve palsy. Materials and methods: One-hundred and fourteen patients treated for facial nerve palsy at our hospital from April 2014-September 2016 were retrospectively reviewed. ENoG was performed 10-16 days after symptom onset. Patients were classified into Groups A (ENoG value 10%-20%, n = 9) and B (ENoG value <10%, n = 21). Eight months after symptom onset, electrophysiological and symptomatic outcomes were evaluated as the aberrant regeneration ratio of the blink reflex and the total synkinesis score of the Sunnybrook facial grading system, respectively. The outcomes of the groups were compared. Results: Group B had a significantly higher median aberrant regeneration ratio (0% versus 87%, p=.015), median total synkinesis score (1 versus 3, p < .001), and incidence of moderate-to-severe synkinesis (0% versus 57.2%, p=.003) than did Group A. Conclusions and significance: Patients with an ENoG value of <10% have higher risks of aberrant regeneration and moderate-to-severe synkinesis than those with an ENoG value of 10%-20%. Patients with ENoG values of <10% may require rehabilitation to prevent synkinesis.


Assuntos
Paralisia de Bell/diagnóstico por imagem , Eletrodiagnóstico/métodos , Paralisia Facial/diagnóstico por imagem , Herpes Zoster da Orelha Externa/diagnóstico por imagem , Sincinesia/diagnóstico por imagem , Sincinesia/etiologia , Adulto , Paralisia de Bell/complicações , Estudos de Coortes , Expressão Facial , Paralisia Facial/terapia , Feminino , Herpes Zoster da Orelha Externa/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Regeneração Nervosa/fisiologia , Neurofisiologia/métodos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Estatísticas não Paramétricas
13.
Biochim Biophys Acta Mol Cell Res ; 1866(10): 1584-1594, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31276697

RESUMO

The ability to regenerate the entire retina and restore lost sight after injury is found in some species and relies mostly on the epigenetic plasticity of Müller glia. To understand the role of mammalian Müller glia as a source of progenitors for retinal regeneration, we investigated changes in gene expression during differentiation of retinal progenitor cells (RPCs) into Müller glia and analyzed the global epigenetic profile of adult Müller glia. We observed significant changes in gene expression during differentiation of RPCs into Müller glia in only a small group of genes and found a high similarity between RPCs and Müller glia on the transcriptomic and epigenomic levels. Our findings also indicate that Müller glia are epigenetically very close to late-born retinal neurons, but not early-born retinal neurons. Importantly, we found that key genes required for phototransduction were highly methylated. Thus, our data suggest that Müller glia are epigenetically very similar to late RPCs; however, obstacles for regeneration of the entire mammalian retina from Müller glia may consist of repressive chromatin and highly methylated DNA in the promoter regions of many genes required for the development of early-born retinal neurons. In addition, DNA demethylation may be required for proper reprogramming and differentiation of Müller glia into rod photoreceptors.


Assuntos
Plasticidade Celular/fisiologia , Epigênese Genética , Regeneração Nervosa/fisiologia , Neuroglia/metabolismo , Animais , Diferenciação Celular , Plasticidade Celular/genética , Metilação de DNA , Expressão Gênica , Código das Histonas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Retina/lesões , Retina/metabolismo , Células Fotorreceptoras Retinianas Bastonetes , Células-Tronco/citologia
14.
Neuron ; 103(4): 642-657.e7, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31255486

RESUMO

Neuronal subtypes show diverse injury responses, but the molecular underpinnings remain elusive. Using transgenic mice that allow reliable visualization of axonal fate, we demonstrate that intrinsically photosensitive retinal ganglion cells (ipRGCs) are both resilient to cell death and highly regenerative. Using RNA sequencing (RNA-seq), we show genes that are differentially expressed in ipRGCs and that associate with their survival and axon regeneration. Strikingly, thrombospondin-1 (Thbs1) ranked as the most differentially expressed gene, along with the well-documented injury-response genes Atf3 and Jun. THBS1 knockdown in RGCs eliminated axon regeneration. Conversely, RGC overexpression of THBS1 enhanced regeneration in both ipRGCs and non-ipRGCs, an effect that was dependent on syndecan-1, a known THBS1-binding protein. All structural domains of the THBS1 were not equally effective; the trimerization and C-terminal domains promoted regeneration, while the THBS type-1 repeats were dispensable. Our results identify cell-type-specific induction of Thbs1 as a novel gene conferring high regenerative capacity.


Assuntos
Regeneração Nervosa/fisiologia , Células Ganglionares da Retina/fisiologia , Trombospondina 1/fisiologia , Animais , Apoptose , Axônios/metabolismo , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Genes Reporter , Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Compressão Nervosa , Traumatismos do Nervo Óptico/genética , Traumatismos do Nervo Óptico/fisiopatologia , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Opsinas de Bastonetes/deficiência , Opsinas de Bastonetes/fisiologia , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/fisiologia , Trombospondina 1/biossíntese , Trombospondina 1/genética , Transcrição Genética
15.
Exp Neurol ; 321: 113015, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31326353

RESUMO

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


Assuntos
Microglia/metabolismo , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Tratos Piramidais/lesões , Recuperação de Função Fisiológica/fisiologia , Animais , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Masculino , Microglia/patologia , Neurônios/patologia , Neurônios Aferentes/metabolismo , Neurônios Aferentes/patologia , Tratos Piramidais/metabolismo , Tratos Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
16.
Plast Reconstr Surg ; 144(2): 178e-188e, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31348332

RESUMO

BACKGROUND: The sensory recovery of the breast remains an undervalued aspect of autologous breast reconstruction. The aim of this study was to evaluate the effect of nerve coaptation on the sensory recovery of the breast following DIEP flap breast reconstruction and to assess the associations of length of follow-up and timing of the reconstruction. METHODS: A prospective comparative study was conducted of all patients who underwent either innervated or noninnervated DIEP flap breast reconstruction and returned for follow-up between September of 2015 and July of 2017. Nerve coaptation was performed to the anterior cutaneous branch of the third intercostal nerve. Semmes-Weinstein monofilaments were used for sensory testing of the native skin and flap skin. RESULTS: A total of 48 innervated DIEP flaps in 36 patients and 61 noninnervated DIEP flaps in 45 patients were tested at different follow-up time points. Nerve coaptation was significantly associated with lower monofilament values in all areas of the reconstructed breast (adjusted difference, -1.2; p < 0.001), which indicated that sensory recovery of the breast was significantly better in innervated compared with noninnervated DIEP flaps. For every month of follow-up, the mean monofilament value decreased by 0.083 in innervated flaps (p < 0.001) and 0.012 in noninnervated flaps (p < 0.001). Nerve coaptation significantly improved sensation in both immediate and delayed reconstructions. CONCLUSIONS: This study demonstrated that nerve coaptation in DIEP flap breast reconstruction is associated with a significantly better sensory recovery in all areas of the reconstructed breast compared with noninnervated flaps. The length of follow-up was significantly associated with the sensory recovery.


Assuntos
Tecido Adiposo/inervação , Mamoplastia/métodos , Transtornos das Sensações/etiologia , Retalhos Cirúrgicos/inervação , Centros Médicos Acadêmicos , Tecido Adiposo/transplante , Adulto , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Angiografia por Ressonância Magnética/métodos , Mamoplastia/efeitos adversos , Mastectomia/métodos , Pessoa de Meia-Idade , Regeneração Nervosa/fisiologia , Países Baixos , Cuidados Pré-Operatórios , Estudos Prospectivos , Recuperação de Função Fisiológica , Medição de Risco , Transtornos das Sensações/fisiopatologia , Retalhos Cirúrgicos/transplante , Fatores de Tempo , Transplante Autólogo/métodos
17.
Bull Exp Biol Med ; 167(3): 413-417, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31350657

RESUMO

A stimulating effect of a combination of hepatocyte growth factor (HGF) and glial neurotrophic factor (GDNF) on the growth of neurites in the spinal ganglion model was demonstrated. The mechanism of neurite growth in the spinal ganglion model is associated with transactivation of HGF c-met receptor in the presence of both HGF and GDNF. The combination of HGF and GDNF significantly activated mitogenic signaling cascade mediated by protein kinases ERK1/2, which can be a mechanism for increasing the number of neurites. Our findings can be used for developing effective methods for restoring impaired peripheral nerve function after traumatic and ischemic injury using a combination of GDNF and HGF.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neuritos/metabolismo , Animais , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Regeneração Nervosa/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-met/metabolismo
18.
PLoS One ; 14(6): e0218667, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220164

RESUMO

In contrast to mammals, retinal ganglion cells (RGC) axons of the optic nerve even in mature zebrafish exhibit a remarkable capacity for spontaneous regeneration. One constraint of using adult zebrafish is the limited ability to visualize the regeneration process in live animals. To dynamically visualize and trace the degree of target specific optic nerve regeneration, we took advantage of the optical transparency still preserved in post developmental larval zebrafish. We developed a rapid and robust assay to physically transect the larval optic nerve and find that by 96 hours post injury RGC axons have robustly regrown onto the optic tectum. We observe functional regeneration by 8 days post injury, and demonstrate that similar to adult zebrafish, optic nerve transection in larval zebrafish does not prominently induce cell death or proliferation of RGC neurons. Furthermore, we find that partial optic nerve transection results in axonal growth predominantly to the original, contralateral tectum, while complete transection results in innervation of both the correct contralateral and 'incorrect' ipsilateral tectum. Axonal tracing reveals that although regenerating axons innervate the 'incorrect' ipsilateral tectum, they successfully target their topographically appropriate synaptic areas. Combined, our results validate post developmental larval zebrafish as a powerful model for optic nerve regeneration, and reveal intricate mechanistic differences between axonal growth, midline guidance and synaptic targeting during zebrafish optic nerve regeneration.


Assuntos
Axônios/fisiologia , Regeneração Nervosa/fisiologia , Nervo Óptico/fisiopatologia , Células Ganglionares da Retina/fisiologia , Colículos Superiores/fisiopatologia , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Larva , Traumatismos do Nervo Óptico/reabilitação , Traumatismos do Nervo Óptico/veterinária , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Peixe-Zebra/crescimento & desenvolvimento
19.
Nat Neurosci ; 22(7): 1046-1052, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182869

RESUMO

Failed regeneration of CNS myelin contributes to clinical decline in neuroinflammatory and neurodegenerative diseases, for which there is an unmet therapeutic need. Here we reveal that efficient remyelination requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state. We propose that impaired microglia death and/or repopulation may underpin dysregulated microglia activation in neurological diseases, and we reveal therapeutic targets to promote white matter regeneration.


Assuntos
Doenças Desmielinizantes/fisiopatologia , Microglia/fisiologia , Regeneração Nervosa/fisiologia , Animais , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Doenças Desmielinizantes/induzido quimicamente , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação , Lisofosfatidilcolinas/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/classificação , Esclerose Múltipla/patologia , Necrose , Nestina/análise , Fagocitose , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA , Substância Branca/fisiologia
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