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This chapter covers axillary and musculocutaneous neuropathies, with a focus on clinically relevant anatomy, electrodiagnostic approaches, etiologic considerations, and management principles. Disorders of the lateral antebrachial cutaneous nerve, a derivative of the musculocutaneous nerve, are also reviewed. We emphasize the importance of objective findings, including the physical examination and electrodiagnostic evaluation in confirming the isolated involvement of each nerve which, along with the clinical history, informs etiologic considerations. Axillary and musculocutaneous neuropathies are both rare in isolation and most frequently occur in the setting of trauma. Less commonly encountered etiologies include external compression or entrapment, neoplastic involvement, or immune-mediated disorders including neuralgic amyotrophy, postsurgical inflammatory neuropathy, multifocal motor neuropathy, vasculitic neuropathy, and multifocal chronic inflammatory demyelinating polyradiculoneuropathy.
Assuntos
Nervo Musculocutâneo , Doenças do Sistema Nervoso Periférico , Humanos , Doenças do Sistema Nervoso Periférico/diagnóstico , Axila , Eletrodiagnóstico/métodosRESUMO
OBJECTIVE: This study was undertaken to explore manipulation of the Myc protein interactome, members of an oncogene group, in enhancing the intrinsic growth of injured peripheral adult postmitotic neurons and the nerves they supply. New approaches to enhance adult neuron growth properties are a key strategy in improving nerve regeneration. METHODS: Expression and impact of Myc interactome members c-Myc, N-Myc, Mad1, and Max were evaluated within naive and "preconditioned" adult sensory neurons and Schwann cells (SCs), using siRNA and transfection of CRISPR/Cas9 or luciferase reporter in vitro. Morphological, behavioral, and electrophysiological indices of nerve regeneration were analyzed in vivo. RESULTS: c-Myc, N-Myc, Max, and Mad were expressed in adult sensory neurons and in partnering SCs. In vitro knockdown (KD) of either Mad1 or Max, competitive inhibitors of Myc, unleashed heightened neurite outgrowth in both naive uninjured or preconditioned adult neurons. In contrast, KD or inhibition of both isoforms of Myc was required to suppress growth. In SCs, Mad1 KD not only enhanced migratory behavior but also conditioned increased outgrowth in separately cultured adult sensory neurons. In vivo, local Mad1 KD improved electrophysiological, behavioral, and structural indices of nerve regeneration out to 60 days of follow-up. INTERPRETATION: Members of the Myc interactome, specifically Mad1, are novel targets for improving nerve regeneration. Unleashing of Myc growth signaling through Mad1 KD enhances the regrowth of both peripheral neurons and SCs to facilitate better regrowth of nerves. ANN NEUROL 2024;96:216-230.
Assuntos
Regeneração Nervosa , Proteínas Proto-Oncogênicas c-myc , Células de Schwann , Células Receptoras Sensoriais , Animais , Regeneração Nervosa/fisiologia , Camundongos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Células de Schwann/fisiologia , Células de Schwann/metabolismo , Células Receptoras Sensoriais/fisiologia , Células Receptoras Sensoriais/metabolismo , Modelos Animais de Doenças , Gânglios Espinais , Camundongos Endogâmicos C57BL , Células Cultivadas , FemininoRESUMO
Common mechanisms of peripheral axon regeneration are recruited following diverse forms of damage to peripheral nerve axons. Whether the injury is traumatic or disease related neuropathy, reconnection of axons to their targets is required to restore function. Supporting peripheral axon regrowth, while not yet available in clinics, might be accomplished from several directions focusing on one or more of the complex stages of regrowth. Direct axon support, with follow on participation of supporting Schwann cells is one approach, emphasized in this review. However alternative approaches might include direct support of Schwann cells that instruct axons to regrow, manipulation of the inflammatory milieu to prevent ongoing bystander axon damage, or use of inflammatory cytokines as growth factors. Axons may be supported by a growing list of growth factors, extending well beyond the classical neurotrophin family. The understanding of growth factor roles continues to expand but their impact experimentally and in humans has faced serious limitations. The downstream signaling pathways that impact neuron growth have been exploited less frequently in regeneration models and rarely in human work, despite their promise and potency. Here we review the major regenerative signaling cascades that are known to influence adult peripheral axon regeneration. Within these pathways there are major checkpoints or roadblocks that normally check unwanted growth, but are an impediment to robust growth after injury. Several molecular roadblocks, overlapping with tumour suppressor systems in oncology, operate at the level of the perikarya. They have impacts on overall neuron plasticity and growth. A second approach targets proteins that largely operate at growth cones. Addressing both sites might offer synergistic benefits to regrowing neurons. This review emphasizes intrinsic aspects of adult peripheral axon regeneration, emphasizing several molecular barriers to regrowth that have been studied in our laboratory.
Assuntos
Axônios , Traumatismos dos Nervos Periféricos , Adulto , Humanos , Axônios/metabolismo , Regeneração Nervosa/fisiologia , Células de Schwann/fisiologia , Neurônios/patologia , Nervos Periféricos , Traumatismos dos Nervos Periféricos/metabolismoRESUMO
Major urinary proteins (MUPs), members of the broader lipocalin protein family, are classified as pheromones that are excreted in male rodent urine to define conspecific territoriality. In screening for differentially regulated mRNA transcripts in a mouse model of type 1 experimental diabetes mellitus (DM), we identified an unexpected upregulation of several closely related MUP transcripts within diabetic sensory dorsal root ganglia (DRG). Both sexes expressed overall MUP protein content as identified by an antibody widely targeting these upregulated family members, and immunohistochemistry identified expression within neurons, satellite glial cells, and Schwann cells. In dissociated adult sensory neurons, knockdown by an siRNA targeting upregulated MUP mRNAs, enhanced neurite outgrowth, indicating a growth-suppressive role, an impact that was synergistic with subnanomolar insulin neuronal signaling. While MUP knockdown did not generate rises in insulin signaling transcripts, the protein did bind to several mitochondrial and glial targets in DRG lysates. Analysis of a protein closely related to MUPs but that is expressed in humans, lipocalin-2, also suppressed growth, but its impact was unrelated to insulin. In a model of chronic type 1 DM, MUP siRNA knockdown improved electrophysiological and behavioral abnormalities of experimental neuropathy. MUPs have actions beyond pheromone signaling in rodents that involve suppression of growth plasticity of sensory neurons. Its hitherto unanticipated actions overlap with those of lipocalin-2 and may identify a common and widely mediated impact on neuron growth properties by members of the lipocalin family. Knockdown of MUP supports the trophic actions of insulin as a strategy that may improve features of type 1 experimental diabetic neuropathy.NEW & NOTEWORTHY New molecular mechanisms are important to unravel and understand diabetic polyneuropathy, a disorder prevalent in over half of persons with diabetes mellitus (DM). MUPs, members of the lipocalin family of molecules, have an unexpected impact on the plasticity of sensory neurons that are targeted in type 1 experimental diabetic neuropathy. This work explores this potential target in neuropathy in the context of the lipocalin family of molecules.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Neuropatias Diabéticas , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Gânglios Espinais/metabolismo , Humanos , Insulina/metabolismo , Lipocalina-2 , Masculino , Camundongos , Feromônios/metabolismo , Proteínas , RNA Interferente Pequeno , Células Receptoras Sensoriais/metabolismoRESUMO
Diabetic polyneuropathy (DPN) is the most common complication of diabetes, yet its pathophysiology has not been established. Accumulating evidence suggests that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays pivotal roles in the regulation of cell growth and survival during diabetic complications. This study aimed to investigate the impact of MALAT1 silencing in dorsal root ganglion (DRG) sensory neurons, using an α-tocopherol-conjugated DNA/RNA heteroduplex oligonucleotide (Toc-HDO), on the peripheral nervous system of diabetic mice. We identified MALAT1 upregulation in the DRG of chronic diabetic mice that suggested either a pathological change or one that might be protective, and systemic intravenous injection of Toc-HDO effectively inhibited its gene expression. However, we unexpectedly noted that this intervention paradoxically exacerbated disease with increased thermal and mechanical nociceptive thresholds, indicating further sensory loss, greater sciatic-tibial nerve conduction slowing, and additional declines of intraepidermal nerve fiber density in the hind paw footpads. Serine/arginine-rich splicing factors, which are involved in pre-mRNA splicing by interacting with MALAT1, reside in nuclear speckles in wild-type and diabetic DRG neurons; MALAT1 silencing was associated with their disruption. The findings provide evidence for an important role that MALAT1 plays in DPN, suggesting neuroprotection and regulation of pre-mRNA splicing in nuclear speckles. This is also the first example in which a systemically delivered nucleotide therapy had a direct impact on DRG diabetic neurons and their axons.
Assuntos
Diabetes Mellitus Experimental , Neuropatias Diabéticas , RNA Longo não Codificante , Animais , Camundongos , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/metabolismo , Gânglios Espinais/metabolismo , Oligonucleotídeos , Precursores de RNA/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismoRESUMO
The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.
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Neuropatias Diabéticas/terapia , Analgésicos Opioides/uso terapêutico , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/fisiopatologia , Humanos , Hiperglicemia/complicações , Hiperlipidemias/complicações , Programas de Rastreamento/métodos , Manejo da Dor/métodos , Prevalência , Qualidade de Vida/psicologia , Fatores de Risco , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêuticoRESUMO
Injuries and diseases of the peripheral nervous system (PNS) are common but frequently irreversible. It is often but mistakenly assumed that peripheral neuron regeneration is robust without a need to be improved or supported. However, axonal lesions, especially those involving proximal nerves rarely recover fully and injuries generally are complicated by slow and incomplete regeneration. Strategies to enhance the intrinsic growth properties of reluctant adult neurons offer an alternative approach to consider during regeneration. Since axons rarely regrow without an intimately partnered Schwann cell (SC), approaches to enhance SC plasticity carry along benefits to their axon partners. Direct targeting of molecules that inhibit growth cone plasticity can inform important regenerative strategies. A newer approach, a focus of our laboratory, exploits tumor suppressor molecules that normally dampen unconstrained growth. However several are also prominently expressed in stable adult neurons. During regeneration their ongoing expression "brakes" growth, whereas their inhibition and knockdown may enhance regrowth. Examples have included phosphatase and tensin homolog deleted on chromosome ten (PTEN), a tumor suppressor that inhibits PI3K/pAkt signaling, Rb1, the protein involved in retinoblastoma development, and adenomatous polyposis coli (APC), a tumor suppressor that inhibits ß-Catenin transcriptional signaling and its translocation to the nucleus. The identification of several new targets to manipulate the plasticity of regenerating adult peripheral neurons is exciting. How they fit with canonical regeneration strategies and their feasibility require additional work. Newer forms of nonviral siRNA delivery may be approaches for molecular manipulation to improve regeneration.
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Symptomatic distal sensory polyneuropathy (sDSP) is common and debilitating in people with HIV/AIDS, leading to neuropathic pain, although the condition's cause is unknown. To investigate biomarkers and associated pathogenic mechanisms for sDSP, we examined plasma miRNA profiles in HIV/AIDS patients with sDSP or without sDSP in 2 independent cohorts together with assessing related pathogenic effects. Several miRNAs were found to be increased in the Discovery Cohort (sDSP, n = 29; non-DSP, n = 40) by array analyses and were increased in patients with sDSP compared with patients without sDSP. miR-455-3p displayed a 12-fold median increase in the sDSP group, which was confirmed by machine learning analyses and verified by reverse transcription PCR. In the Validation Cohort (sDSP n = 16, non-DSP n = 20, healthy controls n = 15), significant upregulation of miR-455-3p was also observed in the sDSP group. Bioinformatics revealed that miR-455-3p targeted multiple host genes implicated in peripheral nerve maintenance, including nerve growth factor (NGF) and related genes. Transfection of cultured human dorsal root ganglia with miR-455-3p showed a concentration-dependent reduction in neuronal ß-III tubulin expression. Human neurons transfected with miR-455-3p demonstrated reduced neurite outgrowth and NGF expression that was reversed by anti-miR-455-3p antagomir cotreatment. miR-455-3p represents a potential biomarker for HIV-associated sDSP and might also exert pathogenic effects leading to sDSP.
Assuntos
Biomarcadores/sangue , Infecções por HIV/complicações , MicroRNAs/sangue , Polineuropatias/complicações , Adulto , Idoso , Estudos de Coortes , Biologia Computacional , Feminino , Gânglios Espinais , HIV , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Adulto JovemRESUMO
Molecules and pathways that suppress growth are expressed in postmitotic neurons, a potential advantage in mature neural networks, but a liability during regeneration. In this work, we probed the APC (adenomatous polyposis coli)-ß-catenin partner pathway in adult peripheral sensory neurons during regeneration. APC had robust expression in the cytoplasm and perinuclear region of adult DRG sensory neurons both before and after axotomy injury. ß-catenin was expressed in neuronal nuclei, neuronal cytoplasm and also in perineuronal satellite cells. In injured dorsal root ganglia (DRG) sensory neurons and their axons, we observed paradoxical APC upregulation, despite its role as an inhibitor of growth whereas ß-catenin was downregulated. Inhibition of APC in adult sensory neurons and activation of ß-catenin, LEF/TCF transcriptional factors were associated with increased neuronal plasticity in vitro. Local knockdown of APC, at the site of sciatic nerve crush injury enhanced evidence for electrophysiological, behavioural and structural regeneration in vivo. This was accompanied by upregulation of ß-catenin. Collectively, the APC-ß-catenin-LEF/TCF transcriptional pathway impacts intrinsic mechanisms of axonal regeneration and neuronal plasticity after injury, offering new options for addressing axon regeneration.
Assuntos
Polipose Adenomatosa do Colo/metabolismo , Gânglios Espinais/fisiologia , Regeneração Nervosa , Transdução de Sinais , beta Catenina/metabolismo , Animais , Axônios , Células Cultivadas , Gânglios Espinais/citologia , Gânglios Espinais/lesões , Gânglios Espinais/patologia , Masculino , Ratos Sprague-Dawley , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologiaRESUMO
It is not generally appreciated that DNA repair machinery has a critical role in the remodeling of neurons that adopt a regenerative phenotype. We identified that breast cancer 1 (BRCA1)-dependent DNA activity, previously well known to repair cancer cells, is active in adult peripheral neurons and Schwann cells during their injury and regeneration response. Temporary or partial loss of BRCA1 or blockade of its intraneuronal nuclear entry impaired outgrowth in neurons in vitro and impacted nerve regeneration and functional recovery in vivo. We found that distal axonal injury triggered a BRCA1-dependent DNA damage response (DDR) signal in neuronal soma. BRCA1 also supported an enabling transcriptional program of injured neurons and supporting Schwann cells. Our findings indicate that BRCA1 offers prominent functional roles in neurons and glial cells including key support for their physical and molecular integrity. Since BRCA1 mutations are common in humans, this function of BRCA1 in peripheral neurons and their glial partners warrants attention.
Assuntos
Envelhecimento/metabolismo , Proteína BRCA1/metabolismo , Dano ao DNA , Regeneração Nervosa/fisiologia , Nervos Periféricos/fisiologia , Animais , Proteína BRCA1/deficiência , Proliferação de Células , Reparo do DNA , Modelos Biológicos , Compressão Nervosa , Neuritos/metabolismo , Estresse Oxidativo , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Células de Schwann/patologia , Células Receptoras Sensoriais/metabolismoRESUMO
The directional trajectory of growing peripheral nerve axons in the adult impacts their successful regeneration to denervated target tissues. Misdirected axons in neuromas, injured nerve trunks, or nerves with attempted repair diminish the success of regeneration. The behavior of adult rodent peripheral sensory neurons in vitro, in turn, is helpful in predicting axonal behavior in vivo. Here, we describe the adaptation of embryonic neuron growth cone turning assays, an important technique in developmental neurobiology, to adult rat sensory neurons. With some key modifications, and selection of subtypes of neurons likely to respond to a purported growth factor, short-term responses to molecular gradients can be analyzed using routine dorsal root ganglion neuronal cell culture techniques. The caveats are that short-term turning does not necessarily reflect on the overall tropic impact of a molecule, particularly if it alters growth cones through intra-axonal translation. Similarly, to understand the trajectory of an axon, it must be in a growth mode, such as that associated with preconditioning from previous injury.
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Axônios/fisiologia , Técnicas de Cultura de Células/métodos , Células Receptoras Sensoriais/citologia , Animais , Células Cultivadas , Masculino , Modelos Biológicos , RatosRESUMO
AlphaB-crystallin (αBC) is a small heat shock protein that is constitutively expressed by peripheral nervous system (PNS) axons and Schwann cells. To determine what role this crystallin plays after peripheral nerve damage, we found that loss of αBC impaired remyelination, which correlated with a reduced presence of myelinating Schwann cells and increased numbers of nonmyelinating Schwann cells. The heat shock protein also seems to regulate the cross-talk between Schwann cells and axons, because expected changes in neuregulin levels and ErbB2 receptor expression after PNS injury were disrupted in the absence of αBC. Such dysregulations led to defects in conduction velocity and motor and sensory functions that could be rescued with therapeutic application of the heat shock protein in vivo. Altogether, these findings show that αBC plays an important role in regulating Wallerian degeneration and remyelination after PNS injury.
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Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Remielinização/fisiologia , Cadeia B de alfa-Cristalina/metabolismo , Animais , Axônios/metabolismo , Axônios/fisiologia , Feminino , Proteínas de Choque Térmico/metabolismo , Camundongos , Bainha de Mielina/metabolismo , Bainha de Mielina/fisiologia , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/fisiopatologia , Receptor ErbB-2/metabolismo , Células de Schwann/fisiologiaRESUMO
INTRODUCTION: Hodgkin lymphoma (HL) is a common lymphoid malignancy rarely associated with Guillain-Barré syndrome (GBS). In most cases, GBS does not precede HL. METHODS: We describe a patient with acute inflammatory demyelinating polyneuropathy who fulfilled criteria for GBS that heralded undiagnosed HL. RESULTS: Cerebrospinal fluid (CSF) studies revealed albuminocytologic dissociation with significant protein elevation (250 mg/dl). The patient worsened during intravenous immunoglobulin (IVIg) therapy. Constitutional symptoms with elevated inflammatory markers prompted further investigation, and imaging revealed an anterior mediastinal mass confirmed on biopsy to be HL. Chemotherapy yielded early clinical improvement. CONCLUSIONS: GBS preceding HL is rare, and this case highlights the importance of considering HL in the setting of GBS. Marked elevations in CSF protein, ongoing deterioration despite administration of IVIg, and constitutional symptoms with elevated inflammatory markers may be clues to possible HL-induced GBS. Muscle Nerve 55: 601-604, 2017.
Assuntos
Síndrome de Guillain-Barré/complicações , Doença de Hodgkin/complicações , Adulto , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/diagnóstico por imagem , Síndrome de Guillain-Barré/terapia , Doença de Hodgkin/líquido cefalorraquidiano , Doença de Hodgkin/diagnóstico por imagem , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Tomografia por Emissão de Pósitrons , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Tomógrafos ComputadorizadosRESUMO
Restoring critical neuronal architecture after peripheral nerve injury is challenging. Although immediate regenerative responses to peripheral axon injury involve the synthesis of regeneration-associated proteins in neurons and Schwann cells, an unfavorable balance between growth facilitatory and growth inhibitory signaling impairs the growth continuum of injured peripheral nerves. Molecules involved with the signaling network of tumor suppressors play crucial roles in shifting the balance between growth and restraint during axon regeneration. An understanding of the molecular framework of tumor suppressor molecules in injured neurons and its impact on stage-specific regeneration events may expose therapeutic intervention points. In this review we discuss how signaling networks of the specific tumor suppressors PTEN, Rb1, p53, p27 and p21 are altered in injured peripheral nerves and how this impacts peripheral nerve regeneration. Insights into the roles and importance of these pathways may open new avenues for improving the neurological deficits associated with nerve injury.
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Regeneração Nervosa , Traumatismos dos Nervos Periféricos/metabolismo , Transdução de Sinais , Animais , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Humanos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismoRESUMO
The differential sensitivity of neurons to phosphatase and tensin homolog's (PTEN) lipid and protein phosphatase actions pose difficulties in defining the exact neuronal phenotype generated by targeting PTEN in neuronal injury. PTEN's biology beyond its phosphatase functions are also emerging. Considering spatial dynamics of PTEN a decisive factor for its mode of action we propose selective targeting of its cytoplasmic fraction a better therapeutic approach in neuronal injury.
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Apoptose/fisiologia , Proteínas dos Microfilamentos/metabolismo , Neurônios/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Animais , Citoplasma/metabolismo , Humanos , Isquemia/metabolismo , Metabolismo dos Lipídeos/fisiologia , Neurônios/citologia , TensinasRESUMO
Diabetes mellitus targets sensory neurons during the development of peripheral neuropathy. While polyneuropathy is often routinely considered as another 'microvascular' complication of diabetes mellitus, this concept may no longer address the complexities and unique qualities of direct neuronal involvement. The list of altered molecules and pathways in diabetic neurons continues to grow and includes those related to structure, neuronal 'stress', and protection. A role for abnormal direct neuronal insulin signaling has emerged as an important contributing factor in neurodegeneration. Finally, important molecular players that influence neuronal and axon growth, such as PTEN (phosphatase and tensin homolog deleted on chromosome 10) are considered. A better mechanistic understanding of the pathogenesis of diabetic polyneuropathy may foster targeted therapies that reverse a long history of therapeutic failures.
Assuntos
Diabetes Mellitus/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Animais , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/fisiopatologia , Humanos , Insulina/fisiologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Regeneração Nervosa , Plasticidade Neuronal , PTEN Fosfo-Hidrolase/metabolismo , Células Receptoras Sensoriais/patologia , Transdução de SinaisRESUMO
Rapid and efficient axon remyelination aids in restoring strong electrochemical communication with end organs and in preventing axonal degeneration often observed in demyelinating neuropathies. The signals from axons that can trigger more effective remyelination in vivo are still being elucidated. Here we report the remarkable effect of delayed brief electrical nerve stimulation (ES; 1 hour @ 20 Hz 5 days post-demyelination) on ensuing reparative events in a focally demyelinated adult rat peripheral nerve. ES impacted many parameters underlying successful remyelination. It effected increased neurofilament expression and phosphorylation, both implicated in axon protection. ES increased expression of myelin basic protein (MBP) and promoted node of Ranvier re-organization, both of which coincided with the early reappearance of remyelinated axons, effects not observed at the same time points in non-stimulated demyelinated nerves. The improved ES-associated remyelination was accompanied by enhanced clearance of ED-1 positive macrophages and attenuation of glial fibrillary acidic protein expression in accompanying Schwann cells, suggesting a more rapid clearance of myelin debris and return of Schwann cells to a nonreactive myelinating state. These benefits of ES correlated with increased levels of brain derived neurotrophic factor (BDNF) in the acute demyelination zone, a key molecule in the initiation of the myelination program. In conclusion, the tremendous impact of delayed brief nerve stimulation on enhancement of the innate capacity of a focally demyelinated nerve to successfully remyelinate identifies manipulation of this axis as a novel therapeutic target for demyelinating pathologies.
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Axônios/metabolismo , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Filamentos Intermediários/metabolismo , Macrófagos/metabolismo , Bainha de Mielina/metabolismo , Tecido Nervoso/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulação Elétrica , Masculino , Proteína Básica da Mielina/metabolismo , Fosforilação , Nós Neurofibrosos/metabolismo , Ratos Wistar , Células de Schwann/metabolismo , Coloração e Rotulagem , Estilbamidinas/metabolismoRESUMO
Peripheral nerve injury is common especially among young individuals. Although injured neurons have the ability to regenerate, the rate is slow and functional outcomes are often poor. Several potential therapeutic agents have shown considerable promise for improving the survival and regenerative capacity of injured neurons. These agents are reviewed within the context of their molecular mechanisms. The PI3K/Akt and Ras/ERK signaling cascades play a key role in neuronal survival. A number of agents that target these pathways, including erythropoietin, tacrolimus, acetyl-l-carnitine, n-acetylcysteine and geldanamycin have been shown to be effective. Trk receptor signaling events that up-regulate cAMP play an important role in enhancing the rate of axonal outgrowth. Agents that target this pathway including rolipram, testosterone, fasudil, ibuprofen and chondroitinase ABC hold considerable promise for human application. A tantalizing prospect is to combine different molecular targeting strategies in complementary pathways to optimize their therapeutic effects. Although further study is needed prior to human trials, these modalities could open a new horizon in the clinical arena that has so far been elusive.
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Regeneração Nervosa/genética , Doenças do Sistema Nervoso Periférico/terapia , Transdução de Sinais/fisiologia , Animais , AMP Cíclico/genética , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Regeneração Nervosa/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
Neurons choose growth pathways with half hearted reluctance, behavior that may be appropriate to maintain fixed long lasting connections but not to regenerate them. We now recognize that intrinsic brakes on regrowth are widely expressed in these hesitant neurons and include classical tumor suppressor molecules. Here, we review how two brakes, PTEN (phosphatase and tensin homolog deleted on chromosome 10) and retinoblastoma emerge as new and exciting knockdown targets to enhance neuron plasticity and improve outcome from damage or disease.