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1.
Life Sci ; 248: 117465, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105707

RESUMO

BACKGROUND: Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. METHODS: In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. RESULTS: FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. CONCLUSION: These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.


Assuntos
Fator 6 de Crescimento de Fibroblastos/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Músculo Esquelético/metabolismo , Traumatismos dos Nervos Periféricos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Regeneração/genética , Animais , Diferenciação Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Fator 6 de Crescimento de Fibroblastos/antagonistas & inibidores , Fator 6 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Denervação Muscular/métodos , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Proteína MyoD/genética , Proteína MyoD/metabolismo , Mioblastos/metabolismo , Mioblastos/patologia , Miogenina/genética , Miogenina/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Nervo Isquiático/lesões
2.
Nat Commun ; 11(1): 869, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054836

RESUMO

Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABAARs and by an α1-to-α2GABAAR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABAAR benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl- extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl- gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAAR-subtypes and restoring Cl- homeostasis.


Assuntos
Analgésicos/farmacologia , Cloretos/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Receptores de GABA-A/fisiologia , Analgesia/métodos , Analgésicos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Fluorbenzenos/metabolismo , Fluorbenzenos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Transporte de Íons/efeitos dos fármacos , Ligantes , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Simportadores/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Triazóis/metabolismo , Triazóis/farmacologia
3.
PLoS One ; 14(12): e0226626, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31877172

RESUMO

Ginkgo biloba leaves extract (GBE) was subjected to neuroprotective-guided fractionation to produce eleven fractions with different polarities and constituents. The intermediate polar fraction was shown to be terpene trilactones-enriched fraction (TEGBE). Out of this fraction, pure ginkgolide B (G-B) was further purified and identified based on its spectral data. The effects of GBE and TEGBE were evaluated in comparison to that of G-B in the crush sciatic nerve injury rat model. To evaluate the neuroprotective effects, sixty Wistar male rats were randomly allocated into 6 groups: naive, sham, crush + normal saline, and three treatment groups; crush + GBE, crush + TEGBE, and crush + G-B. Treatments were given one hour following injury, and once daily for 14 days. Neurobehavioral tests, histomorphological examinations, and immunohistochemical analysis of the sciatic nerve and the spinal cord were performed at weeks 3 and 6 post-injury. GBE, TEGBE and G-B were shown to enhance the functional and sensory behavioral parameters and to protect the histological and the ultrastructural elements in the sciatic nerve. Additionally, all treatments prevented spinal cord neurons from further deterioration. It was shown that G-B has the most significant potential effects among all treatments with values that were nearly comparable to those of sham and naive groups.


Assuntos
Lesões por Esmagamento/tratamento farmacológico , Ginkgolídeos/uso terapêutico , Lactonas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Nervo Isquiático/lesões , Animais , Lesões por Esmagamento/patologia , Masculino , Traumatismos dos Nervos Periféricos/patologia , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia
4.
Ulus Travma Acil Cerrahi Derg ; 25(6): 555-560, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31701508

RESUMO

BACKGROUND: In this study, we aim to assess the safe, risky and high-risky zones by measuring the proximity of the needles to the peroneal and saphenous nerves in millimeters for the repair of tears of the anterior, middle and posterior horns of the medial and lateral menisci at flexion and extension position during inside-out repair technique. METHODS: First, a cadaveric study was conducted on 10 cadaver knees in which both (lateral and medial) menisci were divided into anterior, corpus and posterior with the longitudinal tear simulating in each section. The next phase involved the suture of the simulated tears of the menisci while the knee was at 90° of flexion and full extension. Finally, the distance from the exit points of the K-wire being inserted through meniscal anterior, corpus and posterior tears to the aforementioned nerves was measured with a digital caliper. RESULTS: The distance between K-wire exit points and neurovascular structures concerning corpus and anterior horn tear repair of both menisci were considered far away and not included. However, closer posterior menisci measurements were taken to avoid the risk of iatrogenic nerve injury. The measured distances for lateral meniscus posterior tears were recorded 11±5.2 mm at 90° of flexion and 8±4.5 mm at extension, whereas those recorded 17.3±5.7 mm at 90° of flexion and 13.7±4.7 mm at extension for medial meniscus. These variables were evaluated statistically using a paired t-test; the mean of t value was not considered statistically significant. CONCLUSION: Our results show that the inside-out technique at knee flexion is safe even in the posterior meniscus tears. However, safety distance can be increased with the higher flexion degrees of the knee. Lastly, in posterior meniscal tear repair, we recommend either retractor assisted mini-open technique at knee flexion, or all-inside suture technique, to avoid nerve injury risk in this zone. Although many surgeons do not prefer inside-out techniques for posterior menisci tears, inside-out posterior meniscal repair of both menisci is as safe as an all-inside technique using retractor assisted mini-open technique with the knee at higher than 90° flexion.


Assuntos
Doença Iatrogênica , Meniscos Tibiais , Traumatismos dos Nervos Periféricos , Humanos , Meniscos Tibiais/inervação , Meniscos Tibiais/cirurgia , Procedimentos Ortopédicos/efeitos adversos , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia
5.
Nat Neurosci ; 22(10): 1659-1668, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501573

RESUMO

Neuropathic pain can be a debilitating condition with both sensory and affective components, the underlying brain circuitry of which remains poorly understood. In the present study, a basolateral amygdala (BLA)-prefrontal cortex (PFC)-periaqueductal gray (PAG)-spinal cord pathway was identified that is critical for the development of mechanical and thermal hypersensitivity after peripheral nerve injury. It was shown that nerve injury strengthens synaptic input from the BLA onto inhibitory interneurons located in the prelimbic medial PFC, by virtue of reduced endocannabinoid modulation. These augmented synaptic connections mediate a feedforward inhibition of projections from the PFC to the ventrolateral PAG region and its downstream targets. Optogenetic approaches combined with in vivo pharmacology reveal that these BLA-PFC-PAG connections alter pain behaviors by reducing descending noradrenergic and serotoninergic modulation of spinal pain signals. Thus, a long-range brain circuit was identified that is crucial for pain processing and that can potentially be exploited toward targeting neuropathic pain.


Assuntos
Vias Neurais/patologia , Neuralgia/patologia , Neurônios/patologia , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Temperatura Alta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Neuralgia/psicologia , Optogenética , Substância Cinzenta Periaquedutal/patologia , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/psicologia , Estimulação Física , Córtex Pré-Frontal/patologia , Medula Espinal/patologia , Sinapses/patologia
6.
J Mater Sci Mater Med ; 30(9): 107, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31512084

RESUMO

In the present study, collagen hydrogel containing naringin was fabricated, characterized and used as the scaffold for peripheral nerve damage treatment. The collagen was dissolved in acetic acid, naringin added to the collagen solution, and cross-linked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide powder (EDC; 0.10 mM) to form the hydrogel. The microstructure, swelling behavior, biodegradation, and cyto/hemocompatibility of the fabricated hydrogels were assessed. Finally, the healing efficacy of the prepared collagen hydrogel loaded with naringin on the sciatic nerve crush injury was assessed in the animal model. The characterization results showed that the fabricated hydrogels have a porous structure containing interconnected pores with the average pore size of 90 µm. The degradation results demonstrated that about 70% of the primary weight of the naringin loaded hydrogel had been lost after 4 weeks of storage in PBS. The in vitro study showed that the proliferation of Schwann cells on the collagen/naringin hydrogel was higher than the control group (tissue culture plate) at both 48 and 72 h after cell seeding and even significantly higher than pure collagen 72 h after cell seeding (*p < 0.005, **p < 0.001). The animal study implied that the sciatic functional index reached to -22.13 ± 3.00 at the end of 60th days post-implantation which was statistically significant (p < 0.05) compared with the negative control (injury without the treatment) (-82.60 ± 1.06), and the pure collagen hydrogel (-59.80 ± 3.20) groups. The hot plate latency test, the compound muscle action potential, and wet weight-loss of the gastrocnemius muscle evaluation confirmed the positive effect of the prepared hydrogels on the healing process of the induced nerve injury. In the final, the histopathologic examinations depicted that the collagen/naringin hydrogel group reduced all the histological changes induced from the nerve injury and showed more resemblance to the normal sciatic nerve, with well-arranged fibers and intact myelin sheath. The overall results implied that the prepared collagen/naringin hydrogel can be utilized as a sophisticated alternative to healing peripheral nerve damages.


Assuntos
Colágeno Tipo I/química , Flavanonas/farmacologia , Regeneração Tecidual Guiada/métodos , Hidrogéis/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/fisiologia , Animais , Células Cultivadas , Colágeno Tipo I/farmacologia , Flavanonas/química , Humanos , Hidrogéis/química , Masculino , Teste de Materiais , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/terapia , Ratos , Ratos Wistar , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacos , Células de Schwann/fisiologia , Nervo Isquiático/efeitos dos fármacos , Tecidos Suporte/química , Cicatrização/efeitos dos fármacos
7.
Neurochem Res ; 44(9): 2092-2102, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31377996

RESUMO

The aim of this study was to evaluate the diagnostic efficacy of 18F-FDG PET/MRI in two different peripheral neuropathic pain models using the injured rat sciatic nerves. Twelve rats, with operation on left sciatic nerves, were evenly divided into three groups: sham surgery (control group), crushing injury and chronic constriction injury (CCI) (experimental groups). The nerve damage was assessed at 3 weeks postoperatively using following methods: paw withdrawal threshold values (RevWT), maximum standardized uptake values on PET/MRI images (SUVR), and counting the number of myelinated axons in proximal and distal sites of nerve injury (MAxR). The results were quantified and statistically analyzed. Compared to the control group, the crushing injury demonstrated significant differences in RevWT (p < 0.0001) and SUVR (p = 0.027) and the CCI group demonstrated significant differences in RevWT (p < 0.0001), SUVR (p = 0.001) and MAxR (p = 0.048). There were no significant differences between the two experimental groups for all assessments. Correlation analysis demonstrated that RevWT and SUVR assessments were highly correlated (r = -- 0.710, p = 0.010), and SUVR and MAxR were highly correlated (r = 0.611, p = 0.035). However, there was no significant correlation between RevWT and MAxR. The PET scan may be a valuable imaging modality to enable noninvasive, objective diagnosis of neuropathic pain caused by peripheral nerve injury. Also, MRI fused with PET may help clarify the anatomic location of soft tissue structures, including the peripheral nerves.


Assuntos
Fluordesoxiglucose F18/química , Neuralgia/diagnóstico por imagem , Traumatismos dos Nervos Periféricos/diagnóstico por imagem , Compostos Radiofarmacêuticos/química , Neuropatia Ciática/diagnóstico por imagem , Animais , Radioisótopos de Flúor/química , Imagem por Ressonância Magnética , Masculino , Traumatismos dos Nervos Periféricos/patologia , Tomografia por Emissão de Pósitrons , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Neuropatia Ciática/patologia
8.
Best Pract Res Clin Anaesthesiol ; 33(1): 47-56, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31272653

RESUMO

Nerve injury is a relatively rare but devastating complication of peripheral nerve blockade (PNB). Monitoring injection pressure during PNB is one method advocated to prevent injury by detecting needle tip placement in a noncompliant position (intraneural or abutting the epineurium). Animal studies show that gross neural damage and clinical injury are associated with injection pressures exceeding 15-20 psi. In contrast, pressures <15 psi are associated with an extraneural needle tip position and no histologic or clinical injury. Injection pressure monitoring has been shown to prevent injection against the brachial plexus roots or femoral nerve during peripheral nerve block. Multiple methods are available to monitor injection pressure, and most of them are inexpensive and easy to use. Large-scale registry database or pragmatic trials are indicated to show that injection pressure monitoring reduces injury in a patient setting.


Assuntos
Reação no Local da Injeção/patologia , Monitorização Intraoperatória/métodos , Bloqueio Nervoso/efeitos adversos , Traumatismos dos Nervos Periféricos/patologia , Humanos , Reação no Local da Injeção/etiologia , Reação no Local da Injeção/prevenção & controle , Injeções/efeitos adversos , Bloqueio Nervoso/instrumentação , Traumatismos dos Nervos Periféricos/etiologia , Traumatismos dos Nervos Periféricos/prevenção & controle , Pressão/efeitos adversos , Ultrassonografia de Intervenção/efeitos adversos , Ultrassonografia de Intervenção/métodos
9.
Int J Mol Sci ; 20(12)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226852

RESUMO

The exchange of solutes between the blood and the nerve tissue is mediated by specific and high selective barriers in order to ensure the integrity of the different compartments of the nervous system. At peripheral level, this function is maintained by the Blood Nerve Barrier (BNB) that, in the presence, of specific stressor stimuli can be damaged causing the onset of neurodegenerative processes. An essential component of BNB is represented by the endothelial cells surrounding the sub-structures of peripheral nerves and increasing evidence suggests that endothelial dysfunction can be considered a leading cause of the nerve degeneration. The purpose of this review is to highlight the main mechanisms involved in the impairment of endothelial cells in specific diseases associated with peripheral nerve damage, such as diabetic neuropathy, erectile dysfunction and inflammation of the sciatic nerve.


Assuntos
Barreira Hematoneural/patologia , Neuropatias Diabéticas/patologia , Endotélio/patologia , Disfunção Erétil/patologia , Neuralgia/patologia , Animais , Barreira Hematoneural/metabolismo , Barreira Hematoneural/fisiopatologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/fisiopatologia , Endotélio/metabolismo , Endotélio/fisiopatologia , Disfunção Erétil/metabolismo , Disfunção Erétil/fisiopatologia , Humanos , Masculino , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia
10.
Cells ; 8(6)2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208035

RESUMO

Numerous experimental studies demonstrate that the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases) Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42) are important regulators in somatosensory neurons, where they elicit changes in the cellular cytoskeleton and are involved in diverse biological processes during development, differentiation, survival and regeneration. This review summarizes the status of research regarding the expression and the role of the Rho GTPases in peripheral sensory neurons and how these small proteins are involved in development and outgrowth of sensory neurons, as well as in neuronal regeneration after injury, inflammation and pain perception. In sensory neurons, Rho GTPases are activated by various extracellular signals through membrane receptors and elicit their action through a wide range of downstream effectors, such as Rho-associated protein kinase (ROCK), phosphoinositide 3-kinase (PI3K) or mixed-lineage kinase (MLK). While RhoA is implicated in the assembly of stress fibres and focal adhesions and inhibits neuronal outgrowth through growth cone collapse, Rac1 and Cdc42 promote neuronal development, differentiation and neuroregeneration. The functions of Rho GTPases are critically important in the peripheral somatosensory system; however, their signalling interconnections and partially antagonistic actions are not yet fully understood.


Assuntos
Células Receptoras Sensoriais/patologia , Células Receptoras Sensoriais/fisiologia , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Humanos , Degeneração Neural/patologia , Neuritos/metabolismo , Nociceptividade , Traumatismos dos Nervos Periféricos/patologia
11.
Muscle Nerve ; 60(2): 192-201, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31093982

RESUMO

INTRODUCTION: We recently demonstrated the beneficial effects of 4-aminopyridine (4-AP), a potassium channel blocker, in enhancing remyelination and recovery of nerve conduction velocity and motor function after sciatic nerve crush injury in mice. Although muscle atrophy occurs very rapidly after nerve injury, the effect of 4-AP on muscle atrophy and intrinsic muscle contractile function is largely unknown. METHODS: Mice were assigned to sciatic nerve crush injury and no-injury groups and were followed for 3, 7, and 14 days with/without 4-AP or saline treatment. Morphological, functional, and transcriptional properties of skeletal muscle were assessed. RESULTS: In addition to improving in vivo function, 4-AP significantly reduced muscle atrophy with increased muscle fiber diameter and contractile force. Reduced muscle atrophy was associated with attenuated expression of atrophy-related genes and increased expression of proliferating stem cells. DISCUSSION: These findings provide new insights into the potential therapeutic benefits of 4-AP against nerve injury-induced muscle atrophy and dysfunction. Muscle Nerve 60: 192-201, 2019.


Assuntos
4-Aminopiridina/farmacologia , Lesões por Esmagamento/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Bloqueadores dos Canais de Potássio/farmacologia , Remielinização/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Animais , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Proteína Forkhead Box O1/efeitos dos fármacos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O3/efeitos dos fármacos , Proteína Forkhead Box O3/genética , Camundongos , Proteínas Musculares/efeitos dos fármacos , Proteínas Musculares/genética , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/genética , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/patologia , Regeneração/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Nervo Isquiático/fisiopatologia , Proteínas com Motivo Tripartido/efeitos dos fármacos , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Ubiquitina-Proteína Ligases/genética
12.
World Neurosurg ; 129: e6-e15, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30981793

RESUMO

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) has been observed to have direct protective effects on neurons after stroke in experimental models and in humans. In the present study, the antiapoptotic effects of G-CSF on spinal α-motoneurons after inducement of peripheral sciatic nerve lesions were evaluated in a rat model. METHODS: Of 48 rats, 24 were treated with G-CSF and 24 were treated with glucose 5% solution (control group). The spinal cord of 6 rats in each group were removed at days 1, 4, 7, and 14. The α-motoneurons of spinal cord section L4-L6 were counted and investigated for the expression of choline acetyltransferase (ChAT), G-CSF receptor (G-CSFR), and Bcl-2 and Bax proteins. Additionally, α-motoneuron fluorescence double staining was performed for ChAT/Bcl-2, ChAT/Bax, and ChAT/G-CSFR. RESULTS: Without G-CSF treatment, the number of ChAT-positive α-motoneurons on the lesion side was significantly decreased (P < 0.001). The number of α-motoneurons with Bcl-2 and G-CSFR positivity on the lesion side was significantly decreased (P < 0.05). In contrast, the number of α-motoneurons with Bax positivity was significantly greater (P < 0.05). After G-CSF treatment, the differences in the number of α-motoneurons on the 2 sides were not statistically significant. Fluorescence double staining of α-motoneurons was positive for ChAT/Bcl-2, ChAT/Bax, and ChAT/G-CSFR. CONCLUSION: The results indicated that G-CSF has neuroprotective properties in spinal α-motoneurons and contributes to antiapoptotic effects after peripheral nerve lesions. The relevance of G-CSF, its precise mode of action, and the effect of these findings in clinical situations remains to be elucidated and require examination in further studies.


Assuntos
Apoptose/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismos dos Nervos Periféricos/patologia , Animais , Masculino , Neurônios Motores/patologia , Ratos , Ratos Sprague-Dawley
13.
Mol Neurobiol ; 56(10): 7085-7096, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30976982

RESUMO

Fibroblast growth factor-inducible-14 (Fn14), a receptor for tumor necrosis-like weak inducer of apoptosis, is expressed in the neurons of dorsal root ganglion (DRG). Its mRNA is increased in the injured DRG following peripheral nerve injury. Whether this increase contributes to neuropathic pain is unknown. We reported here that peripheral nerve injury caused by spinal nerve ligation (SNL) increased the expression of Fn14 at both protein and mRNA levels in the injured DRG. Blocking this increase attenuated the development of SNL-induced mechanical, thermal, and cold pain hypersensitivities. Conversely, mimicking this increase produced the increases in the levels of phosphorylated extracellular signal-regulated kinase ½ and glial fibrillary acidic protein in ipsilateral dorsal horn and the enhanced responses to mechanical, thermal, and cold stimuli in the absence of SNL. Mechanistically, the increased Fn14 activated the NF-κB pathway through promoting the translocation of p65 into the nucleus of the injured DRG neurons. Our findings suggest that Fn14 may be a potential target for the therapeutic treatment of peripheral neuropathic pain.


Assuntos
NF-kappa B/metabolismo , Neuralgia/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais , Receptor de TWEAK/metabolismo , Animais , Células Cultivadas , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Ligadura , Masculino , Camundongos , Microinjeções , Neuralgia/patologia , Limiar da Dor , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Nervos Espinhais/metabolismo , Nervos Espinhais/patologia
14.
Pain ; 160(5): 1146-1155, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30920428

RESUMO

Oxytocin reduces primary sensory afferent excitability and produces analgesia in part through a peripheral mechanism, yet its actions on physiologically characterized, mechanically sensitive afferents in normal and neuropathic conditions are unknown. We recorded intracellularly from L4 dorsal root ganglion neurons characterized as low-threshold mechanoreceptors (LTMRs) or high-threshold mechanoreceptors (HTMRs) in female rats 1 week after L5 partial spinal nerve injury or sham control (n = 24 rats/group) before, during, and after ganglionic perfusion with oxytocin, 1 nM. Nerve injury desensitized and hyperpolarized LTMRs (membrane potential [Em] was -63 ± 1.8 mV in sham vs -76 ± 1.4 mV in nerve injury; P < 0.001), and sensitized HTMRs without affecting Em. In nerve-injured rats, oxytocin depolarized LTMRs towards normal (Em = -69 ± 1.9 mV) and, in 6 of 21 neurons, resulted in spontaneous action potentials. By contrast, oxytocin hyperpolarized HTMRs (Em = -68 ± 2.7 mV before vs -80 ± 3.2 mV during oxytocin exposure; P < 0.01). These effects were reversed after removal of oxytocin, and oxytocin had minimal effects in neurons from sham surgery animals. Sensory afferent neurons immunopositive for the vasopressin 1a receptor were larger (34 ± 6.3 µm, range 16-57 µm) than immunonegative neurons (26 ± 3.4 µm, range 15-43 µm; P < 0.005). These data replicate findings that neuropathic injury desensitizes LTMRs while sensitizing HTMRs and show rapid and divergent oxytocin effects on these afferent subtypes towards normal, potentially rebalancing input to the central nervous system. Vasopressin 1a receptors are present on medium to large diameter afferent neurons and could represent oxytocin's target.


Assuntos
Gânglios Espinais/patologia , Nociceptores/efeitos dos fármacos , Ocitocina/uso terapêutico , Traumatismos dos Nervos Periféricos/patologia , Células Receptoras Sensoriais/efeitos dos fármacos , Tato , Potenciais de Ação/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Feminino , Mecanorreceptores/efeitos dos fármacos , Nociceptores/fisiologia , Ocitocina/farmacologia , Limiar da Dor/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/metabolismo , Células Receptoras Sensoriais/fisiologia
15.
Histochem Cell Biol ; 152(2): 109-117, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30927067

RESUMO

To assess the potential role of IL-6 in sciatic nerve injury-induced activation of a pro-regenerative state in remote dorsal root ganglia (DRG) neurons, we compared protein levels of SCG-10 and activated STAT3, as well as axon regeneration in IL-6 knockout (IL-6ko) mice and their wild-type (WT) counterparts. Unilateral sciatic nerve compression and transection upregulated SCG-10 protein levels and activated STAT3 in DRG neurons not only in lumbar but also in cervical segments of WT mice. A pro-regenerative state induced by prior sciatic nerve lesion in cervical DRG neurons of WT mice was also shown by testing for axon regeneration in crushed ulnar nerve. DRG neurons from IL-6ko mice also displayed bilaterally increased levels of SCG-10 and STAT3 in both lumbar and cervical segments after sciatic nerve lesions. However, levels of SCG-10 protein in lumbar and cervical DRG of IL-6ko mice were significantly lower than those of their WT counterparts. Sciatic nerve injury induced a lower level of SCG-10 in cervical DRG of IL-6ko than WT mice, and this correlates with significantly shorter regeneration of axons distal to the crushed ulnar nerve. These results suggest that IL-6 contributes, at the very least, to initiation of the neuronal regeneration program in remote DRG neurons after unilateral sciatic nerve injury.


Assuntos
Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Interleucina-6/metabolismo , Regeneração Nervosa , Neurônios/citologia , Neurônios/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Animais , Western Blotting , Proteínas de Ligação ao Cálcio , Gânglios Espinais/patologia , Gânglios Espinais/cirurgia , Imuno-Histoquímica , Interleucina-6/análise , Interleucina-6/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/química , Neurônios/patologia , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/cirurgia , Fator de Transcrição STAT3/análise
16.
PLoS One ; 14(3): e0213586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870492

RESUMO

We evaluated whether chronic administration of LIMK2-inhibitors could improve erectile function by alleviating CVOD through suppressing cavernosal fibrosis in a rat model of cavernosal nerve crush-injury (CNCI). Forty-two 12-week-old rats were equally categorized into the three groups: sham-surgery (S), CNCI (I), and CNCI treated with LIMK2-inhibitors (L). The L-group was treated with daily intraperitoneal injection of LIMK2-inhibitors (10.0 mg/kg) for 30-days after surgery. Erectile function was assessed using dynamic-infusion-cavernosometry (DIC). Penile tissue was processed for Masson's-trichrome staining, Western-blotting, and double immunofluorescence. The I-group showed significantly higher maintenance and drop rates as well as lower papaverine response, compared to the S-group. Chronic inhibition of LIMK2 in the L-group significantly improved the DIC parameters compared to those in the I-group, although the parameters were not completely restored to normal control values. Also, the I-group showed a reduced smooth muscle (SM)-to-collagen ratio, decreased immunohistochemical staining for α-SM-actin, increased number of fibroblasts positive for phosphorylated Cofilin, increased LIMK2/Cofilin phosphorylation and increased protein expression of Collagen-1 or Fibronectin, compared to the S-group. The L-group showed significant improvements in SM/collagen ratio and the deposition of Collagen-1 or Fibronectin compared to the I-group, although not completely normalized. According to the densitometry and confocal microscopy results, the L-group showed restoration of LIMK2/Cofilin phosphorylation and amount of fibroblasts positive for phosphorylated Cofilin to the normal control value. In conclusion, chronic inhibition of LIMK2 can improve CVOD and ED by alleviating cavernosal fibrosis via normalizing the LIMK2/Cofilin pathway.


Assuntos
Disfunção Erétil , Quinases Lim , Pênis , Traumatismos dos Nervos Periféricos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Animais , Modelos Animais de Doenças , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/enzimologia , Disfunção Erétil/patologia , Fibrose , Quinases Lim/antagonistas & inibidores , Quinases Lim/metabolismo , Masculino , Pênis/enzimologia , Pênis/patologia , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/enzimologia , Traumatismos dos Nervos Periféricos/patologia , Ratos
17.
Theranostics ; 9(3): 734-746, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809305

RESUMO

Motor endplates (MEPs) are the important interfaces between peripheral nerves and muscle fibers. Investigation of the spatial distribution of MEPs could help us better understand neuromuscular functional activities and improve the diagnosis and therapy of related diseases. Methods: Fluorescent α-bungarotoxin was injected to label the motor endplates in whole-mount skeletal muscles, and tissue optical clearing combined with light-sheet microscopy was used to investigate the spatial distribution of MEPs and in-muscle nerve branches in different skeletal muscles in wild-type and transgenic fluorescent mice. Electrophysiology was used to determine the relationship between the spatial distribution of MEPs and muscle function. Results: The exact three-dimensional distribution of MEPs in whole skeletal muscles was first obtained. We found that the MEPs in the muscle were distributed in an organized pattern of lamella clusters, with no MEPs outside the lamella zone. Each MEP lamella was innervated by one independent in-muscle nerve branch and mediated an independent muscle subgroup contraction. Additionally, the MEPs changed along the lamella clusters after denervation and regained the initial pattern after reinnervation. The integrity and spatial distribution of MEPs could reflect the functional state of muscles. The signal absence of a certain MEP lamella could suggest a problem in certain part of the muscle. Conclusions: The MEP lamella clusters might be the basis of neuromuscular function, and the spatial distribution of MEPs could serve as a testbed for evaluating the functional status of muscle and the therapeutic targeting map related to MEPs.


Assuntos
Placa Motora/anatomia & histologia , Músculo Esquelético/anatomia & histologia , Potenciais de Ação , Animais , Bungarotoxinas , Carbocianinas , Imageamento Tridimensional , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia de Fluorescência , Placa Motora/fisiologia , Denervação Muscular , Músculo Esquelético/lesões , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Traumatismos dos Nervos Periféricos/diagnóstico por imagem , Traumatismos dos Nervos Periféricos/patologia
18.
PLoS Genet ; 15(2): e1007982, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30779743

RESUMO

Following injury, axons of the peripheral nervous system have retained the capacity for regeneration. While it is well established that injury signals require molecular motors for their transport from the injury site to the nucleus, whether kinesin and dynein motors play additional roles in peripheral nerve regeneration is not well understood. Here we use genetic mutants of motor proteins in a zebrafish peripheral nerve regeneration model to visualize and define in vivo roles for kinesin and dynein. We find that both kinesin-1 and dynein are required for zebrafish peripheral nerve regeneration. While loss of kinesin-1 reduced the overall robustness of axonal regrowth, loss of dynein dramatically impaired axonal regeneration and also reduced injury-induced Schwann cell remodeling. Chimeras between wild type and dynein mutant embryos demonstrate that dynein function in neurons is sufficient to promote axonal regrowth. Finally, by simultaneously monitoring actin and microtubule dynamics in regenerating axons we find that dynein appears dispensable to initiate axonal regrowth, but is critical to stabilize microtubules, thereby sustaining axonal regeneration. These results reveal two previously unappreciated roles for dynein during peripheral nerve regeneration, initiating injury induced Schwann cell remodeling and stabilizing axonal microtubules to sustain axonal regrowth.


Assuntos
Dineínas/fisiologia , Regeneração Nervosa/fisiologia , Nervos Periféricos/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Axônios/fisiologia , Axônios/ultraestrutura , Dineínas/genética , Cinesina/genética , Cinesina/fisiologia , Mutação , Regeneração Nervosa/genética , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Células de Schwann/citologia , Células de Schwann/fisiologia , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/genética
19.
BMC Genomics ; 20(1): 147, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782122

RESUMO

BACKGROUND: Pain is a subjective experience derived from complex interactions among biological, environmental, and psychosocial pathways. Sex differences in pain sensitivity and chronic pain prevalence are well established. However, the molecular basis underlying these sex dimorphisms are poorly understood particularly with regard to the role of the peripheral nervous system. Here we sought to identify shared and distinct gene networks functioning in the peripheral nervous systems that may contribute to sex differences of pain in rats after nerve injury. RESULTS: We performed RNA-seq on dorsal root ganglia following chronic constriction injury of the sciatic nerve in male and female rats. Analysis from paired naive and injured tissues showed that 1513 genes were differentially expressed between sexes. Genes which facilitated synaptic transmission in naïve and injured females did not show increased expression in males. CONCLUSIONS: Appreciating sex-related gene expression differences and similarities in neuropathic pain models may help to improve the translational relevance to clinical populations and efficacy of clinical trials of this major health issue.


Assuntos
Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Regulação da Expressão Gênica , Traumatismos dos Nervos Periféricos/etiologia , Animais , Feminino , Perfilação da Expressão Gênica , Masculino , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Ratos , Fatores Sexuais , Transcriptoma
20.
Exp Neurol ; 315: 60-71, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30731076

RESUMO

Peripheral nerve regeneration following injury is often incomplete, resulting in significant personal and socioeconomic costs. Although a conditioning crush lesion prior to surgical nerve transection and repair greatly promotes nerve regeneration and functional recovery, feasibility and ethical considerations have hindered its clinical applicability. In a recent proof of principle study, we demonstrated that conditioning electrical stimulation (CES) had effects on early nerve regeneration, similar to that seen in conditioning crush lesions (CCL). To convincingly determine its clinical utility, establishing the effects of CES on target reinnervation and functional outcomes is of utmost importance. In this study, we found that CES improved nerve regeneration and reinnervation well beyond that of CCL. Specifically, compared to CCL, CES resulted in greater intraepidermal skin and NMJ reinnervation, and greater physiological and functional recovery including mechanosensation, compound muscle action potential on nerve conduction studies, normalization of gait pattern, and motor performance on the horizontal ladder test. These findings have direct clinical relevance as CES could be delivered at the bedside before scheduled nerve surgery.


Assuntos
Terapia por Estimulação Elétrica , Regeneração Nervosa , Potenciais de Ação , Animais , Marcha , Masculino , Compressão Nervosa , Condução Nervosa , Junção Neuromuscular/patologia , Traumatismos dos Nervos Periféricos/patologia , Desempenho Psicomotor , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Sensação , Pele/inervação
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