Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 736
Filtrar
1.
Neurochem Res ; 44(9): 2123-2138, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31376053

RESUMO

Number of ligations made in the chronic constriction injury (CCI) neuropathic pain model has raised serious concerns. We compared behavioural responses, nerve morphology and expression of pain marker, c-fos among CCI models developed with one, two, three and four ligations. The numbers of ligation(s) on sciatic nerve shows no significant difference in displaying mechanical and cold allodynia, and mechanical and thermal hyperalgesia throughout 84 days. All groups underwent similar levels of nerve degeneration post-surgery. Similar c-fos level in brain cingulate cortex, parafascicular nuclei and amygdala were observed in all CCI models compared to sham-operated group. Therefore, number of ligations does not impact intensity of pain symptoms, pathogenesis and neuronal activation. A single ligation is sufficient to develop neuropathic pain, in contrast to the established model of four ligations. This study dissects and characterises the CCI model, ascertaining a more uniform animal model to surrogate actual neuropathic pain condition.


Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos ICR , Neuralgia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Animais , Constrição Patológica/complicações , Giro do Cíngulo/metabolismo , Giro do Cíngulo/patologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Núcleos Intralaminares do Tálamo/metabolismo , Núcleos Intralaminares do Tálamo/patologia , Ligadura , Masculino , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Medição da Dor , Proteínas Proto-Oncogênicas c-fos/metabolismo , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Neuropatia Ciática/etiologia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia
2.
J Bone Joint Surg Am ; 101(6): 523-530, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30893233

RESUMO

BACKGROUND: Peripheral nerve compression and entrapment can be debilitating. Using a validated animal model of peripheral nerve compression, we examined the utility of 2 drugs approved for other uses in humans, 4-aminopyridine (4-AP) and erythropoietin (EPO), as treatments for surgically induced ischemia and as adjuvants to surgical decompression. METHODS: Peripheral nerve compression was induced in wild-type mice by placing an inert silicone sleeve around the sciatic nerve. Decompression surgery was performed at 6 weeks with mice receiving 4-AP, EPO, or saline solution either during and after compression or only after decompression. A nerve conduction study and morphometric analyses were performed to compare the extent of the injury and the efficacy of the therapies, and the findings were subjected to statistical analysis. RESULTS: During peripheral nerve compression, there was a progressive decline in nerve conduction velocity compared with that in sham-treatment animals, in which nerve conduction velocity remained normal (∼55 m/s). Mice treated with 4-AP or EPO during the compression phase had significantly smaller declines in nerve conduction velocity and increased plateau nerve conduction velocities compared with untreated controls (animals that received saline solution). Histomorphometric analyses of newly decompressed nerves (i.e., nerves that underwent decompression on the day that the mouse was sacrificed) revealed that both treated groups had significantly greater proportions of large (>5-µm) axons than the untreated controls. Following surgical decompression, all animals recovered to a normal baseline nerve conduction velocity by day 15; however, treatment significantly accelerated improvement (in both the 4-AP and the EPO group), even when it was only started after decompression. Histomorphometric analyses at 7 and 15 days following surgical decompression revealed significantly increased myelin thickness and significantly greater proportions of large axons among the treated animals. CONCLUSIONS: Both the 4-AP and the EPO-treated group demonstrated improvements in tissue architectural and electrodiagnostic measurements, both during and after peripheral nerve compression, compared with untreated mice. CLINICAL RELEVANCE: Peripheral nerve decompression is one of the most commonly performed procedures in orthopaedic surgery. We believe that there is reason for some optimism about the translation of our findings to the clinical setting. Our findings in this murine model suggest that 4-AP and EPO may lessen the effects of nerve entrapment and that the use of these agents after decompression may speed and perhaps otherwise optimize recovery after surgery.


Assuntos
4-Aminopiridina/uso terapêutico , Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Síndromes de Compressão Nervosa/terapia , Bloqueadores dos Canais de Potássio/uso terapêutico , Neuropatia Ciática/terapia , Animais , Descompressão Cirúrgica , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndromes de Compressão Nervosa/fisiopatologia , Condução Nervosa/fisiologia , Neuropatia Ciática/fisiopatologia
3.
Muscle Nerve ; 59(6): 679-682, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30897216

RESUMO

INTRODUCTION: Neuropathy after total knee arthroplasty (TKA) can cause significant morbidity but is inconsistently reported. METHODS: We reviewed the clinical, electrodiagnostic and perioperative features of all patients who underwent primary TKA at our institution and developed a new neuropathy within 8 weeks postoperatively. RESULTS: Fifty-four cases were identified (incidence 0.37% [95% confidence interval, 0.28-0.49]) affecting the following nerve(s): peroneal (37), sciatic (11), ulnar (2), tibial (2), sural (1), and lumbosacral plexus (1). In all cases with follow-up data, motor recovery typically occurred within 1 year and was complete or near-complete. CONCLUSIONS: Post-TKA neuropathy is uncommon, typically does not require intervention and usually resolves within 1 year. Post-TKA neuropathy most often affects the nerves surgically at risk. Anesthesia type does not correlate with post-TKA neuropathy. An inflammatory etiology for post-TKA neuropathy is rare but should be considered in specific cases. Muscle Nerve 59:679-682, 2019.


Assuntos
Artroplastia do Joelho , Doenças do Sistema Nervoso Periférico/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Idoso , Feminino , Humanos , Plexo Lombossacral , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Doenças do Sistema Nervoso Periférico/fisiopatologia , Neuropatias Fibulares/epidemiologia , Neuropatias Fibulares/fisiopatologia , Complicações Pós-Operatórias/fisiopatologia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Neuropatia Ciática/epidemiologia , Neuropatia Ciática/fisiopatologia , Nervo Sural , Neuropatia Tibial/epidemiologia , Neuropatia Tibial/fisiopatologia , Neuropatias Ulnares/epidemiologia , Neuropatias Ulnares/fisiopatologia
4.
Mol Biol Rep ; 46(2): 1963-1972, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30783935

RESUMO

Polymyxin is a critical antibiotic against the infection caused by multidrug-resistant gram-negative bacteria. Neurotoxicity is one of main dose-limiting factors. The present study aimed to investigate the underlying molecular mechanism on colistin induced peripheral neurotoxicity using a mouse model. Forty mice were divided into control, colistin 1-, 3- and 7-day groups, the mice were intravenously injected with saline or colistin (sulfate) at the dose of 15 mg/kg/day for 1, 3 and 7 days, respectively. The results showed that, colistin treatment for 7 days markedly resulted in the demyelination, axonal degeneration and mitochondria swelling in the mice's sciatic tissues. Colistin treatment induces oxidative stress as well as the increases of mitochondrial permeability transition, decreases of membrane potential (ΔΨm) and activities of mitochondrial respiratory chain in the mice's sciatic nerve tissues. Furthermore, in the colistin-7 day group, adenosine-triphosphate (ATP) level Na+/K+-ATPase activity decreased to 75.2% (p < 0.01) and 80.1% (p < 0.01), respectively. Meanwhile, colistin treatment down-regulates the expression of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) mRNAs and up-regulates the expression of Bax and caspase-3 mRNAs. Our results reveal that colistin induced sciatic nerves damage involves oxidative stress, mitochondrial dysfunction and the inhibition of Akt/mTOR pathway.


Assuntos
Colistina/metabolismo , Colistina/farmacologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , China , Colistina/toxicidade , Feminino , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo , Neuropatia Ciática/induzido quimicamente , Neuropatia Ciática/fisiopatologia
5.
Neurol Res ; 41(4): 326-334, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30638158

RESUMO

OBJECTIVE: To verify the action of sericin associated to swim exercise with overload, on sciatic nerve repair in Wistar rats, after 22 days of nerve compression. METHODS: Forty animals been composed of five groups: control, injury, injury-sericin, injury-swimming and injury-sericin-swimming. During the lesion procedure, sericin, in hydrolyzed form, applied directly to the injury in the injury-sericin and injury-sericin-swimming groups. Injury-swimming and injury-sericin-swimming groups underwent to 5 days per week for 3 weeks, with a 10% overload of the animal's body weight, and a weekly progressive evolution of swimming time, lasting 15, 20 and 25 min/day. Pre and throughout the treatment period the animals performed evaluation of sciatic functional index and pressure pain threshold with digital von Frey filament. Euthanasia was performed on the 22nd postoperative day, and two fragments of the nerve were collected and prepared for descriptive and quantitative analysis. RESULTS: The sciatic functional index assessment showed significant differences in the motor function of the control until the 14th day. Regarding the allodynia, there was revealed a significant improvement in injury-swimming performance relative to injury, injury-sericin and injury-sericin-swimming, and the number of viable and non-viable nerve fibers smaller than 4 µm in diameter was significantly higher in the injury-sericin-swimming. CONCLUSION: swimming showed a better evolution of the nociceptive threshold and allodynia. Sericin treatment had exacerbated pro-inflammatory characteristics. On the other hand, the association of sericine and swimming showed a possible regulatory effect by resting swimming exercise, with a significant increase of fibers of smaller diameter.


Assuntos
Condicionamento Físico Animal/métodos , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/reabilitação , Sericinas/uso terapêutico , Natação , Animais , Modelos Animais de Doenças , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Ratos , Ratos Wistar , Nervo Isquiático/patologia , Neuropatia Ciática/fisiopatologia , Sericinas/metabolismo , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Resultado do Tratamento
6.
Eur J Pain ; 23(4): 835-842, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30582875

RESUMO

BACKGROUND: Hypersensitivity and altered sweating are often present in neuropathy patients. Nerve lesions are known to produce sudomotor dysfunctions but also patients suffering from complex regional pain syndrome, CRPS1-a condition without a nerve lesion-present with sweating disorders. METHODS: Using proton nuclear magnetic resonance of sweat water, we quantified sweat output of mice suffering from a nerve lesion or a bone fracture without nerve lesion and correlated their sweating with behavioural paw hypersensitivity accessed in von Frey testings, water applications and weight-bearing measured with an incapacitance metre. RESULTS: Lesioned animals sweat less and are hypersensitive compared to healthy controls, as expected. Fractured animals on the injured side sweat less acutely after the injury but more in the chronic phase. They are hypersensitive acutely as well as chronically after the fracture. These findings resemble human bone trauma patients in the acute phase and CRPS patients in the chronic phase. CONCLUSIONS: Sweating disorders are present both in neuropathic animals and in those with a bone fracture without nerve lesions, and autonomic dysfunctions might be considered as an important component in the aetiology of neuropathies. SIGNIFICANCE: Sweat output changes in mice after bone trauma, potentially indicative of posttraumatic processes leading to CRPS in humans.


Assuntos
Fraturas Ósseas/fisiopatologia , Neuralgia/fisiopatologia , Distrofia Simpática Reflexa/fisiopatologia , Neuropatia Ciática/fisiopatologia , Sudorese/fisiologia , Animais , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Síndromes da Dor Regional Complexa/etiologia , Síndromes da Dor Regional Complexa/fisiopatologia , Feminino , Fraturas Ósseas/complicações , Camundongos , Espectroscopia de Prótons por Ressonância Magnética , Distrofia Simpática Reflexa/etiologia
8.
Glia ; 66(11): 2487-2502, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30306639

RESUMO

The transition of differentiated Schwann cells to support of nerve repair after injury is accompanied by remodeling of the Schwann cell epigenome. The EED-containing polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 methylation and represses key nerve repair genes such as Shh, Gdnf, and Bdnf, and their activation is accompanied by loss of H3K27 methylation. Analysis of nerve injury in mice with a Schwann cell-specific loss of EED showed the reversal of polycomb repression is required and a rate limiting step in the increased transcription of Neuregulin 1 (type I), which is required for efficient remyelination. However, mouse nerves with EED-deficient Schwann cells display slow axonal regeneration with significantly low expression of axon guidance genes, including Sema4f and Cntf. Finally, EED loss causes impaired Schwann cell proliferation after injury with significant induction of the Cdkn2a cell cycle inhibitor gene. Interestingly, PRC2 subunits and CDKN2A are commonly co-mutated in the transition from benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST's). RNA-seq analysis of EED-deficient mice identified PRC2-regulated molecular pathways that may contribute to the transition to malignancy in neurofibromatosis.


Assuntos
Proliferação de Células/fisiologia , Regulação da Expressão Gênica/genética , Regeneração Nervosa/efeitos dos fármacos , Complexo Repressor Polycomb 2/metabolismo , Células de Schwann/fisiologia , Neuropatia Ciática/fisiopatologia , Animais , Proliferação de Células/efeitos dos fármacos , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Regeneração Nervosa/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurregulinas/metabolismo , Proteína Oncogênica v-akt/metabolismo , Complexo Repressor Polycomb 2/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Células de Schwann/efeitos dos fármacos , Células de Schwann/ultraestrutura , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
9.
Sci Rep ; 8(1): 13585, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206259

RESUMO

Rodent models of sciatic nerve lesion are regularly used to assess functional deficits in nerves. Impaired locomotor functions induced by sciatic nerve lesion are currently evaluated with scoring systems despite their limitations. To overcome these shortcomings, which includes low sensitivity, little significance, and the representation of only marginal components of motion profiles, some additional metrics have been introduced. However, a quantitative determination of motion deficits is yet to be established. We used a three-dimensional motion analysis to investigate gait deficits after sciatic nerve lesion in rats. This enabled us to depict the distorted gait motion using both traditional parameters and novel readouts that are specific for the three-dimensional analysis. Our results suggest that three-dimensional motion analysis facilitates a comprehensive understanding of the gait impairment specifically, but not limited to, a sciatic lesion rat model. A broad application of these methods will improve understanding and standardized motor assessment.


Assuntos
Fenômenos Biomecânicos/fisiologia , Marcha/fisiologia , Locomoção/fisiologia , Recuperação de Função Fisiológica/fisiologia , Nervo Isquiático/lesões , Neuropatia Ciática/fisiopatologia , Animais , Interpretação Estatística de Dados , Masculino , Regeneração Nervosa/fisiologia , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Nervo Isquiático/fisiopatologia
10.
Einstein (Sao Paulo) ; 16(3): eAO4206, 2018 Sep 17.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30231143

RESUMO

OBJECTIVE: To evaluate the effects of right sciatic nerve compression and cryotherapy on muscle tissue. METHODS: We used 42 male Wistar rats, subdivided in the following Groups Control, Injury 3, Injury 8 and Injury 15 submitted to nerve compression and euthanized in the 3rd, 8th and 15th day after surgery. The Cryotherapy Injury 3 was entailed treatment with cryotherapy by immersion of the animal in recipient for 20 minutes during 1 day, then animals were euthanized at the 3rd day after surgery, and the Cryotherapy Injury 8 and the Cryotherapy Injury 15 was treated for 6 days, and euthanized at the 8th and 15th day after surgery. Functional evaluation was performed by the grasping strength of the right pelvic limb. The right tibialis anterior muscles were evaluated for mass, smaller diameter and cross-sectional area. In the Cryotherapy Injury 8 and the Cryotherapy Injury 15 groups, the hydroxyproline was dosed in the right soles. RESULTS: In the compression there was a significant difference in the Injury Groups compared with the Control Group (p<0.05). In the smaller diameter, the compression in Control Group was higher than Injury 8 (p=0.0094), Injury 15 (p=0.002) and Cryotherapy Injury 15 (p<0.001) groups. The comparison between groups with euthanasia in the same post-operative period, a significant difference (p=0.0363) was seen in day 8th after surgery, and this result in Cryotherapy Injury Group was greater than Injury Group. In the fiber area, Control Group was also higher than the Injury 8 (p=0.0018), the Injury 15 (p<0.001) and the Cryotherapy Injury 15 (p<0.001). In hydroxyproline, no significant difference was seen between groups. CONCLUSION: Nerve damage resulted in decreased muscle strength and trophism, the cryotherapy delayed hypotrophy, but this effect did not persist after cessation of treatment.


Assuntos
Crioterapia/métodos , Síndromes de Compressão Nervosa/patologia , Síndromes de Compressão Nervosa/terapia , Nervo Isquiático/patologia , Neuropatia Ciática/patologia , Neuropatia Ciática/terapia , Animais , Modelos Animais de Doenças , Hipertrofia/fisiopatologia , Masculino , Debilidade Muscular/fisiopatologia , Síndromes de Compressão Nervosa/fisiopatologia , Distribuição Aleatória , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Nervo Isquiático/fisiopatologia , Nervo Isquiático/cirurgia , Neuropatia Ciática/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
11.
Sci Rep ; 8(1): 11179, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-30046125

RESUMO

Peripheral nerve injury can result in the decreased quality of life and bring us economic burden on society and individuals. Wallerian degeneration (WD) is critical for nerve degeneration and regeneration, but the mechanisms of WD are still elusive. Here, we report the effect of Toll-like receptor 4 (TLR4) on cultured Schwann cells (SCs) in vitro. The data showed that TLR4 expression was up-regulated after sciatic nerve injury of rat. TLR4 was expressed in cultured SCs. Enhanced or silenced expression of TLR4 affected SC proliferation, migration, apoptosis and relative gene expression. Furthermore, altered expression of TLR4 resulted in expression changes in c-Jun, ERK and catenin but not AKT and c-Fos pathways in SCs. These results suggested that TLR4 may be an important effective target in peripheral nerve degeneration and/or regeneration during WD in future investigations.


Assuntos
Traumatismos dos Nervos Periféricos/genética , Neuropatia Ciática/genética , Receptor 4 Toll-Like/genética , Degeneração Walleriana/genética , Animais , Apoptose/genética , Movimento Celular/genética , Células Cultivadas , Regulação da Expressão Gênica/genética , Humanos , Regeneração Nervosa/genética , Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/fisiopatologia , Transdução de Sinais/genética , Degeneração Walleriana/fisiopatologia
12.
Medicine (Baltimore) ; 97(23): e11051, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29879074

RESUMO

RATIONALE: Peripheral neuropathy is a rare complication of carbon monoxide intoxication. Peripheral neuropathy following carbon monoxide intoxication is known to completely recover within a few months. PATIENT CONCERNS: A 40-year-old man complained of motor weakness and hypoesthesia of the right lower extremity with swelling of his right thigh after carbon monoxide intoxication resulting from a suicide attempt. DIAGNOSES: Following nerve conduction and electromyographic studies, the patient was diagnosed with sciatic neuropathy with severe axonopathy. Clinical and laboratory findings led to a diagnosis of rhabdomyolysis. INTERVENTIONS: The patient was treated conservatively for rhabdomyolysis and underwent comprehensive rehabilitation for sciatic neuropathy during hospitalization. OUTCOMES: After discharge, he underwent serial follow-up tests with nerve conduction and electromyographic studies, which showed prolonged persistence of sciatic neuropathy; however, he showed significant improvement at his 26-month post-discharge follow-up. LESSON: Patients presenting with peripheral neuropathy secondary to carbon monoxide intoxication may show variable recovery periods; however, a favorable prognosis can be expected regardless of the concomitant occurrence of rhabdomyolysis and/or compartment syndrome.


Assuntos
Intoxicação por Monóxido de Carbono/complicações , Monóxido de Carbono/toxicidade , Rabdomiólise/etiologia , Neuropatia Ciática/etiologia , Adulto , Síndromes Compartimentais/diagnóstico , Síndromes Compartimentais/etiologia , Eletromiografia/métodos , Humanos , Masculino , Condução Nervosa/fisiologia , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Rabdomiólise/diagnóstico , Rabdomiólise/terapia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/reabilitação , Tentativa de Suicídio/psicologia , Resultado do Tratamento
13.
Int J Mol Sci ; 19(5)2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29735961

RESUMO

Ultra-fine bubbles (<200 nm in diameter) have several unique properties and have been tested in various medical fields. The purpose of this study was to investigate the effects of oxygen ultra-fine bubbles (OUBs) on a sciatic nerve crush injury (SNC) model rats. Rats were intraperitoneally injected with 1.5 mL saline, OUBs diluted in saline, or nitrogen ultra-fine bubbles (NUBs) diluted in saline three times per week for 4 weeks in four groups: (1) control, (sham operation + saline); (2) SNC, (crush + saline); (3) SNC+OUB, (crush + OUB-saline); (4) SNC+NUB, (crush + NUB-saline). The effects of the OUBs on dorsal root ganglion (DRG) neurons and Schwann cells (SCs) were examined by serial dilution of OUB medium in vitro. Sciatic functional index, paw withdrawal thresholds, nerve conduction velocity, and myelinated axons were significantly decreased in the SNC group compared to the control group; these parameters were significantly improved in the SNC+OUB group, although NUB treatment did not affect these parameters. In vitro, OUBs significantly promoted neurite outgrowth in DRG neurons by activating AKT signaling and SC proliferation by activating ERK1/2 and JNK/c-JUN signaling. OUBs may improve nerve dysfunction in SNC rats by promoting neurite outgrowth in DRG neurons and SC proliferation.


Assuntos
Microbolhas/uso terapêutico , Oxigênio/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Neuropatia Ciática/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Masculino , Compressão Nervosa , Regeneração Nervosa/efeitos dos fármacos , Oxigênio/administração & dosagem , Ratos Wistar , Células de Schwann/efeitos dos fármacos , Células de Schwann/patologia , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/fisiopatologia
14.
Lasers Med Sci ; 33(6): 1341-1349, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29611064

RESUMO

To analyze the effect of photobiomodulation and dexamethasone on nerve regeneration after a sciatic nerve crushing model. Twenty-six Swiss mice were divided into the following groups: naive; sham; injured, low-level laser therapy (LLLT) (660 nm, 10 J/cm2, 0.6 J, 16.8 J total energy emitted during the 28 days of radiation, 20 s, for 28 days); dexamethasone (Dex) (local injection of 2 mg/kg for 10 consecutive days); and LLLT group associated with Dex (LLLT/Dex), with the same parameters of the other groups. For nerve injury, a portable adjustable pinch was used. The animals were evaluated using the Sciatic Functional Index (SFI) and Sciatic Static Index (SSI). The results obtained were evaluated with Image J™ and Kinovea™. Data and images were obtained at baseline and after 7, 14, 21, and 28 days after surgery. The evaluation of hyperalgesia, using Hargreaves, and behavior through the open field was also performed. In functional and static analysis, all groups presented significant differences when compared to the injured group. In the analysis of the SSI results, the group treated with both LLLT and dexamethasone was more effective in improving the values of this parameter, and in the SFI, the laser-treated group obtained better results. In the evaluation through the open field and the Hargreaves, there was no difference. The application of LLLT and dexamethasone was effective in nerve regeneration according to the results and was more effective when LLLT was associated with dexamethasone than in LLLT alone for the SSI.


Assuntos
Dexametasona/uso terapêutico , Terapia com Luz de Baixa Intensidade/métodos , Nervo Isquiático/lesões , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/radioterapia , Animais , Dexametasona/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Regeneração Nervosa/fisiologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/efeitos da radiação , Neuropatia Ciática/fisiopatologia
15.
J Neurosci ; 38(20): 4829-4839, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29695413

RESUMO

The medial prefrontal cortex (mPFC) plays a major role in both sensory and affective aspects of pain. There is extensive evidence that chronic pain produces functional changes within the mPFC. However, our understanding of local circuit changes to defined subpopulations of mPFC neurons in chronic pain models remains unclear. A major subpopulation of mPFC neurons project to the periaqueductal gray (PAG), which is a key midbrain structure involved in endogenous pain suppression and facilitation. Here, we used laser scanning photostimulation of caged glutamate to map cortical circuits of retrogradely labeled cortico-PAG (CP) neurons in layer 5 (L5) of mPFC in brain slices prepared from male mice having undergone chronic constriction injury (CCI) of the sciatic nerve. Whole-cell recordings revealed a significant reduction in excitability for L5 CP neurons contralateral to CCI in the prelimbic (PL), but not infralimbic (IL), region of mPFC. Circuit mapping showed that excitatory inputs to L5 CP neurons in both PL and IL arose primarily from layer 2/3 (L2/3) and were significantly reduced in CCI mice. Glutamate stimulation of L2/3 and L5 elicited inhibitory inputs to CP neurons in both PL and IL, but only L2/3 input was significantly reduced in CP neurons of CCI mice. We also observed significant reduction in excitability and L2/3 inhibitory input to CP neurons ipsilateral to CCI. These results demonstrating region and laminar specific changes to mPFC-PAG neurons suggest that a unilateral CCI bilaterally alters cortical circuits upstream of the endogenous analgesic network, which may contribute to persistence of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a significant unresolved medical problem that is refractory to traditional analgesics and can negatively affect emotional health. The role of central circuits in mediating the persistent nature of chronic pain remains unclear. Local circuits within the medial prefrontal cortex (mPFC) process ascending pain inputs and can modulate endogenous analgesia via direct projections to the periaqueductal gray (PAG). However, the mechanisms by which chronic pain alters intracortical circuitry of mPFC-PAG neurons are unknown. Here, we report specific changes to local circuits of mPFC-PAG neurons in mice displaying chronic pain behavior after nerve injury. These findings provide evidence for a neural mechanism by which chronic pain disrupts the descending analgesic system via functional changes to cortical circuits.


Assuntos
Vias Neurais/fisiopatologia , Neuralgia/fisiopatologia , Neurônios , Substância Cinzenta Periaquedutal/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Mapeamento Encefálico/métodos , Ácido Glutâmico/metabolismo , Sistema Límbico/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor , Técnicas de Patch-Clamp , Estimulação Luminosa , Neuropatia Ciática/fisiopatologia
16.
Prog Neuropsychopharmacol Biol Psychiatry ; 84(Pt A): 257-266, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29524514

RESUMO

The persistent activation of N-methyl-d-aspartate acid receptors (NMDARs) seems to be responsible for a series of changes in neurons associated with neuropathic pain, including the failure of opioids that act through mu-opioid receptors (MORs) to provide efficacious pain relief. As the noradrenergic locus coeruleus (LC) forms part of the endogenous analgesic system, we explored how intra-LC administration of morphine, a MORs agonist, alone or in combination with MK-801, a NMDARs antagonist, affects the sensorial and affective dimension of pain in a rat model of neuropathic pain; chronic constriction injury (CCI). Intra-LC microinjection of morphine induced analgesia in CCI rats, as evident in the von Frey and cold plate test 7 and 30 days after surgery, although it was not able to reverse pain-related aversion when evaluated using the place escape/avoidance test. However, the thermal anti-nociception produced by morphine was enhanced when it was administered to the LC of CCI animals in combination with MK-801, without altering its effects on the mechanical thresholds. Furthermore, pain-related aversion was reduced by co-administration of these agents, yet only in the short-term CCI (7 day) rats. Overall the data indicate that administration of morphine to the LC produces analgesia in nerve injured animals and that this effect is potentiated in specific pain modalities by the co-administration of MK-801. While a combination of morphine and MK-801 could reduce pain-related aversion in short-term neuropathic animals, it was ineffective in the long-term, suggesting that its sensorial effects and its influence on the affective component of pain are regulated by different mechanisms.


Assuntos
Analgésicos Opioides/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Locus Cerúleo/efeitos dos fármacos , Morfina/farmacologia , Neuralgia/tratamento farmacológico , Animais , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Constrição Patológica , Modelos Animais de Doenças , Quimioterapia Combinada , Locus Cerúleo/fisiopatologia , Masculino , Neuralgia/fisiopatologia , Neuralgia/psicologia , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/fisiopatologia , Dor Nociceptiva/psicologia , Ratos Sprague-Dawley , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/psicologia
17.
Sci Rep ; 8(1): 5219, 2018 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-29581478

RESUMO

Axon degeneration underlies many nervous system diseases; therefore understanding the regulatory signalling pathways is fundamental to identifying potential therapeutics. Previously, we demonstrated heparan sulphates (HS) as a potentially new target for promoting CNS repair. HS modulate cell signalling by both acting as cofactors in the formation of ligand-receptor complexes and in sequestering ligands in the extracellular matrix. The enzyme heparanase (Hpse) negatively regulates these processes by cleaving HS and releasing the attached proteins, thereby attenuating their ligand-receptor interaction. To explore a comparative role for HS in PNS axon injury/repair we data mined published microarrays from distal sciatic nerve injury. We identified Hpse as a previously unexplored candidate, being up-regulated following injury. We confirmed these results and demonstrated inhibition of Hpse led to an acceleration of axonal degeneration, accompanied by an increase in ß-catenin. Inhibition of ß-catenin and the addition of Heparinase I both attenuated axonal degeneration. Furthermore the inhibition of Hpse positively regulates transcription of genes associated with peripheral neuropathies and Schwann cell de-differentiation. Thus, we propose Hpse participates in the regulation of the Schwann cell injury response and axo-glia support, in part via the regulation of Schwann cell de-differentiation and is a potential therapeutic that warrants further investigation.


Assuntos
Glucuronidase/genética , Traumatismos dos Nervos Periféricos/genética , Nervo Isquiático/metabolismo , Neuropatia Ciática/genética , beta Catenina/genética , Animais , Axônios/metabolismo , Axônios/patologia , Membrana Celular/genética , Membrana Celular/patologia , Matriz Extracelular/genética , Matriz Extracelular/patologia , Regulação da Expressão Gênica/genética , Glucuronidase/metabolismo , Heparitina Sulfato/genética , Heparitina Sulfato/metabolismo , Humanos , Regeneração Nervosa , Neuroglia/metabolismo , Neuroglia/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Traumatismos dos Nervos Periféricos/terapia , Ratos , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/crescimento & desenvolvimento , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Transdução de Sinais/genética
18.
Drug Des Devel Ther ; 12: 171-177, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29398906

RESUMO

Purpose: Recent evidence has shown the involvement of inflammation in the development of diabetic peripheral neuropathy (DPN). MicroRNA-146a (miR-146a) is closely involved in the inflammatory response. However, the role of miR-146a in the inflammatory reaction in DPN has not been clarified. This study was designed to explore the role of miR-146a in the regulation of inflammatory responses in DPN. Methods: Rats were randomly divided into three groups (n=6 per group): control group, type 2 diabetes mellitus (T2DM) group and DPN group. T2DM and DPN rats were intraperitoneally injected with streptozotocin. Sciatic nerve conduction velocity (NCV) was determined at the 6th week and the 12th week in each group. The expression of microRNAs was detected by quantitative real-time polymerase chain reaction in three sciatic nerves for each group of rats. Expression of inflammatory cytokines in nerve tissues and plasma was measured by Western blot and Bio-Plex Pro™ assays. Results: The NCV and expression levels of miR-146a in the DPN group were significantly decreased (P<0.01) compared to the other two groups. Expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the DPN group was significantly increased compared with the control and T2DM groups (P<0.01). Pearson's correlation analysis showed that the expression level of miR-146a was negatively correlated with the levels of IL-1ß, TNF-α and NF-κB. Conclusion: miR-146a is involved in the pathogenesis of DPN, and its expression level is closely related to the inflammatory responses that aggravate sciatic nerve injuries.


Assuntos
Neuropatias Diabéticas/genética , Inflamação/genética , MicroRNAs/genética , Neuropatia Ciática/genética , Animais , Citocinas/biossíntese , Citocinas/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/fisiopatologia , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Masculino , NF-kappa B/genética , Condução Nervosa , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/fisiopatologia
19.
Pain ; 159(3): 526-539, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29447134

RESUMO

A strong link between histone deacetylases (HDACs) and nociceptive hypersensitivity has been indicated in different pain models. However, the underlying molecular and cellular mechanisms remain elusive. Here, we discovered that partial sciatic nerve ligation-induced mechanical allodynia and thermal hyperalgesia in mice were associated with increased mRNA and protein expressions of HDAC5 (a member of class IIa HDACs) and SRY-related HMG-box 10 (SOX10) in the ipsilateral lumbar dorsal horn. Gene knockdown of spinal HDAC5 or SOX10 attenuated partial sciatic nerve ligation-induced nociceptive hypersensitivity, companied with decrease of spinal neuronal sensitization markers, namely phosphorylated-Erk, phosphorylated-GluN1 (ser896), and c-Fos. Conversely, overexpression of spinal HDAC5 or SOX10 by lentiviruses in naive mice not only induced pain-like behaviors but also increased the expression of these spinal neuronal sensitization markers. Of note, in contrast to its conventional deacetylation effect to silence gene expression, overexpression of HDAC5 not only enhanced SOX10 expression but also induced nociceptive hypersensitivity in naive mice, which were reversed by SOX10 gene knockdown. Chromatin-immunoprecipitation assay further confirmed a novel nonhistone modulation function of HDACs on SOX10 expression, that is, HDAC5 regulates SOX10 by binding to the promoter region of Sox10 gene. In conclusion, this study for the first time demonstrates that HDAC5 regulates spinal neuronal sensitization in neuropathic pain by upregulating modulating SOX10 expression. Thus, interventions that reduce HDAC5/SOX10 expression may represent promising avenues in the treatment of neuropathic pain.


Assuntos
Regulação da Expressão Gênica/genética , Histona Desacetilases/metabolismo , Fatores de Transcrição SOXE/metabolismo , Neuropatia Ciática/metabolismo , Animais , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Medição da Dor/métodos , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/administração & dosagem , Fatores de Transcrição SOXE/genética , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Corno Dorsal da Medula Espinal/metabolismo , Transdução Genética
20.
J Comp Neurol ; 526(7): 1195-1208, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29405296

RESUMO

Nerves are particularly vulnerable to damage due to their unique structure with meter-long axons. In the peripheral nervous system neurons and Schwann cells can activate the injury-response program that directs axons to either regenerate or degenerate after traumatic nerve injury. However, the differences between the genetic programs driving nerve regeneration and degeneration have not yet been described extensively. To understand these differences, in this study we have compared the injury-induced transcriptomic changes between the regenerating proximal segment and the degenerating distal segment of a transected nerve, at different post-injury time points. We analyzed the spatiotemporal dynamics of the mouse transcriptome using a sciatic nerve-injury model by means of RNA sequencing. The results of the differentially regulated genes (DEGs) analysis show that some DEG groups are similarly regulated in both proximal and distal segments, and primarily display a positive correlation. However, some DEG groups are exclusively regulated in either the proximal or the distal segment, suggesting that these DEG groups constitute a genetic network for distinguishing the regenerative and degenerative responses. In addition, our gene ontology analysis revealed an enrichment of particular biological processes in different phases and locations. Thus, our data provide a spatiotemporal profile of the transcriptomes that are differentially regulated in either regenerating or degenerating nerves, in vivo. The specific biological processes enriched in the DEG groups might delineate the injury-responsive program that induces contrasting regenerative and degenerative responses in different nerve segments.


Assuntos
Regulação da Expressão Gênica/fisiologia , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Transcriptoma/fisiologia , Animais , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Feminino , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Redes Reguladoras de Genes , Cinesina/genética , Cinesina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA