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1.
Diagn Pathol ; 13(1): 18, 2018 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-29499721

RESUMO

BACKGROUND: Ischemic fasciitis is a distinctive pseudosarcomatous entity with a marked predilection for elderly and physically debilitated or immobilized patients. The etiology of these lesions is unknown but felt to be related to ischemic vascular events. CASE PRESENTATION: Herein, we report for the first time, two cytogenetic translocations, t(1;2)(p36.1;q23) and t(7;19)(q32;q13.3) in a 75 year-old ambulating female with a history of left total hip arthroplasty 20 years ago. CONCLUSION: These translocations suggest a possible clonal pathogenetic link though their significance remains to be established.


Assuntos
Cromossomos Humanos , Fasciite/patologia , Síndrome do Músculo Piriforme/genética , Síndrome do Músculo Piriforme/patologia , Ciática/genética , Ciática/patologia , Translocação Genética/genética , Idoso , Fasciite/diagnóstico , Fasciite/genética , Feminino , Humanos , Isquemia/genética , Síndrome do Músculo Piriforme/diagnóstico , Ciática/diagnóstico
2.
J Cell Physiol ; 233(6): 4815-4824, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29150958

RESUMO

Many studies have reported that microRNAs participate in neuropathic pain development. Previously, miR-200b and miR-429 are reported to be involved in various diseases. In our current study, we focused on their roles in neuropathic pain and we found that miR-200b and miR-429 were significantly decreased in chronic constriction injury (CCI) rat spinal cords and isolated microglials. miR-200b and miR-429 overexpression were able to relieve neuropathic pain through modulating PWT and PWL in CCI rats. Meanwhile, we observed that both miR-200b and miR-429 upregulation could repress neuroinflammation via inhibiting inflammatory cytokines such as IL-6, IL-1ß, and TNF-α in CCI rats. By carry out bioinformatics technology, Zinc finger E box binding protein-1 (ZEB1) was predicted as target of miR-200b, and miR-429 and dual-luciferase reporter assays confirmed the correlation between them. ZEB1 has been reported to regulate a lot of diseases. Here, we found that ZEB1 was greatly increased in CCI rats and miR-200b and miR-429 overexpression markedly suppressed ZEB1 mRNA expression in rat microglial cells. In addition, knockdown of ZEB1 can reduce neuropathic pain development and co-transfection of LV-anti-miR-200b/miR-429 reversed this phenomenon in vivo. Taken these together, our results suggested that miR-200b/miR-429 can serve as an important regulator of neuropathic pain development by targeting ZEB1.


Assuntos
MicroRNAs/metabolismo , Microglia/metabolismo , Limiar da Dor , Ciática/metabolismo , Medula Espinal/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Antagomirs/genética , Antagomirs/metabolismo , Comportamento Animal , Citocinas/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , MicroRNAs/genética , Percepção da Dor , Ratos Sprague-Dawley , Ciática/genética , Ciática/fisiopatologia , Ciática/prevenção & controle , Transdução de Sinais , Medula Espinal/fisiopatologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
3.
Nat Commun ; 8: 14265, 2017 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28223688

RESUMO

Lumbar disc herniation (LDH) is common and often debilitating. Microdiscectomy of herniated lumbar discs (LDHsurg) is performed on the most severe cases to resolve the resulting sciatica. Here we perform a genome-wide association study on 4,748 LDHsurg cases and 282,590 population controls and discover 37 highly correlated markers associating with LDHsurg at 8q24.21 (between CCDC26 and GSDMC), represented by rs6651255[C] (OR=0.81; P=5.6 × 10-12) with a stronger effect among younger patients than older. As rs6651255[C] also associates with height, we performed a Mendelian randomization analysis using height polygenic risk scores as instruments to estimate the effect of height on LDHsurg risk, and found that the marker's association with LDHsurg is much greater than predicted by its effect on height. In light of presented findings, we speculate that the effect of rs6651255 on LDHsurg is driven by susceptibility to developing severe and persistent sciatica upon LDH.


Assuntos
Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença , Variação Genética , Degeneração do Disco Intervertebral/genética , Deslocamento do Disco Intervertebral/genética , Vértebras Lombares/patologia , Ciática/genética , Adulto , Sequência de Bases , Estatura/genética , Demografia , Feminino , Loci Gênicos , Humanos , Degeneração do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
4.
BMC Musculoskelet Disord ; 17(1): 500, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27964712

RESUMO

BACKGROUND: The aim of the present study was to provide an overview of the literature addressing the role of genetic factors and biomarkers predicting pain recovery in newly diagnosed lumbar radicular pain (LRP) patients. METHODS: The search was performed in Medline OVID, Embase, PsycInfo and Web of Science (2004 to 2015). Only prospective studies of patients with LRP addressing the role of genetic factors (genetic susceptibility) and pain biomarkers (proteins in serum) were included. Two independent reviewers extracted the data and assessed methodological quality. RESULTS: The search identified 880 citations of which 15 fulfilled the inclusion criteria. Five genetic variants; i.e., OPRM1 rs1799971 G allele, COMT rs4680 G allele, MMP1 rs1799750 2G allele, IL1α rs1800587 T allele, IL1RN rs2234677 A allele, were associated with reduced recovery of LRP. Three biomarkers; i.e., TNFα, IL6 and IFNα, were associated with persistent LRP. CONCLUSION: The present results indicate that several genetic factors and biomarkers may predict slow recovery in LRP. Still, there is a need for replication of the findings. A stricter use of nomenclature is also highly necessary. TRIAL REGISTRATION: The review is registered PROSPERO 20th of November 2015. Registration number is CRD42015029125 .


Assuntos
Catecol O-Metiltransferase/genética , Predisposição Genética para Doença , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/genética , Metaloproteinase 1 da Matriz/genética , Receptores Opioides mu/genética , Ciática/genética , Alelos , Biomarcadores/sangue , Pessoas com Deficiência , Humanos , Interferon-alfa/sangue , Interleucina-6/sangue , Dor Lombar/epidemiologia , Dor Lombar/genética , Região Lombossacral , Polimorfismo de Nucleotídeo Único , Prevalência , Ciática/sangue , Ciática/epidemiologia , Fator de Necrose Tumoral alfa/sangue
5.
PLoS One ; 11(10): e0163877, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27764105

RESUMO

Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6-7%) than in other European populations (1-2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Ciática/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9 , Bases de Dados Factuais , Suscetibilidade a Doenças , Finlândia , Frequência do Gene , Genótipo , Humanos , Fatores de Transcrição NFI/genética , Polimorfismo de Nucleotídeo Único , Ciática/patologia
6.
J Tradit Chin Med ; 36(6): 784-8, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-29949712

RESUMO

OBJECTIVE: To investigate the effect and underlying mechanisms of combined medicated thread moxibustion therapy plus needle picking therapy of Zhuang nationality medicine on antioxidant levels in a rat model of sciatica. METHODS: One hundred Wistar rats, of specific pathogen free level, were randomly divided into five groups: normal control group, model group, medicated thread moxibustion group, needle picking group, and combination group. Each group contained 20 rats. In the model, medicated thread moxibustion, needle picking, and combination groups, sciatica models were established through chronic constriction injury of the sciatic nerve. After the model was established, the rats in the medicated thread moxibustion, needle picking, and combination groups were given the corresponding therapies for 21 days. The control and model groups received no treatment. Reactive oxygen species, superoxide dismutase, malondialdehyde, and total antioxidant capacity changes were determined. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NADPH oxidases 4 (NOX4) mRNA expression and the morphology of cells were observed to detect apoptosis of gamma- aminobutyric acid ergic (GABAergic) neurons. RESULTS: Compared with control group, reactive oxygen species and malondialdehyde levels rose significantly in the model group (P < 0.01), while superoxide dismutase and total antioxidant capacity levels were lowered (P < 0.05). Compared with the model group, reactive oxygen species and malondialdehyde decreased in the needle picking group (P < 0.05), while superoxide dismutase levels were increased (P < 0.05); reactive oxygen species and malondialdehyde significantly decreased in the combination group (P < 0.01). In addition, the model group had higher NOX4 mRNA expression than that of the control group (P < 0.05), and the combination group had lower expression levels than that of the model group (P < 0.05). Apoptosis of GABAergic neurons was observed in the model group, and was attenuated after combined therapy. CONCLUSION: The medicated thread moxibustion therapy plus needle picking therapy of Zhuang nationality medicine can prevent oxidative damage in the rat model of sciatica via down-regulating NOX4 expression, improving antioxidant capacity, and inhibiting the oxidative damage pathway of GABAergic neurons.


Assuntos
Terapia por Acupuntura , Moxibustão , Ciática/terapia , Pontos de Acupuntura , Animais , Antioxidantes/metabolismo , Terapia Combinada , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Malondialdeído/metabolismo , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Ciática/genética , Ciática/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
7.
Anesth Analg ; 122(1): 264-72, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26418124

RESUMO

BACKGROUND: Mitochondria play an important role in many cellular and physiologic functions. Mitochondria are dynamic organelles, and their fusion and fission regulate cellular signaling, development, and mitochondrial homeostasis. The most common complaint of human immunodeficiency virus (HIV)-sensory neuropathy is pain on the soles in patients with HIV, but the exact molecular mechanisms of HIV neuropathic pain are not clear. In the present study, we investigated the role of mitochondrial dynamin-related protein 1 (Drp1, a GTPase that mediates mitochondrial fission) in the perineural HIV coat glycoprotein gp120-induced neuropathic pain state. METHODS: Neuropathic pain was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. Mechanical threshold was tested using von Frey filaments. The mechanical threshold response was assessed over time using the area under curves. Intrathecal administration of antisense oligodeoxynucleotide (ODN) against Drp1, mitochondrial division inhibitor-1 (mdivi-1), or phenyl-N-tert-butylnitrone (a reactive oxygen species scavenger) was given. The expression of spinal Drp1 was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging. RESULTS: Intrathecal administration of either antisense ODN against Drp1 or mdivi-1 decreased mechanical allodynia (a sensation of pain evoked by nonpainful stimuli) in the gp120 model. Intrathecal ODN or mdivi-1 did not change basic mechanical threshold in sham surgery rats. Intrathecal Drp1 antisense ODN decreased the spinal expression of increased Drp1 protein induced by peripheral gp120 application. Intrathecal phenyl-N-tert-butylnitrone reduced mechanical allodynia. Furthermore, both intrathecal Drp1 antisense ODN and mdivi-1 reversed the upregulation of mitochondrial superoxide in the spinal dorsal horn in the gp120 neuropathic pain state. CONCLUSIONS: These data suggest that mitochondrial division plays a substantial role in the HIV gp120-related neuropathic pain state through mitochondrial reactive oxygen species and provides evidence for a novel approach to treating chronic pain in patients with HIV.


Assuntos
Analgésicos/farmacologia , Óxidos N-Cíclicos/farmacologia , Dinaminas/metabolismo , Depuradores de Radicais Livres/farmacologia , Proteína gp120 do Envelope de HIV , Hiperalgesia/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Oligonucleotídeos Antissenso/metabolismo , Células do Corno Posterior/efeitos dos fármacos , Quinazolinonas/farmacologia , Ciática/prevenção & controle , Superóxidos/metabolismo , Analgésicos/administração & dosagem , Animais , Óxidos N-Cíclicos/administração & dosagem , Modelos Animais de Doenças , Dinaminas/genética , Depuradores de Radicais Livres/administração & dosagem , Infecções por HIV/complicações , Infecções por HIV/virologia , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Hiperalgesia/virologia , Injeções Espinhais , Masculino , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/genética , Limiar da Dor/efeitos dos fármacos , Células do Corno Posterior/metabolismo , Quinazolinonas/administração & dosagem , Ratos Sprague-Dawley , Proteínas Recombinantes , Ciática/genética , Ciática/metabolismo , Ciática/fisiopatologia , Ciática/virologia , Fatores de Tempo
8.
Glia ; 64(5): 730-42, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26712109

RESUMO

As lysosomal hydrolysis has long been suggested to be responsible for myelin clearance after peripheral nerve injury, in this study, we investigated the possible role of autophagolysosome formation in myelin phagocytosis by Schwann cells and its final contribution to nerve regeneration. We found that the canonical formation of autophagolysosomes was induced in demyelinating Schwann cells after injury, and the inhibition of autophagy via Schwann cell-specific knockout of the atg7 gene or pharmacological intervention of lysosomal function caused a significant delay in myelin clearance. However, Schwann cell dedifferentiation, as demonstrated by extracellular signal-regulated kinase activation and c-Jun induction, and redifferentiation were not significantly affected, and thus the entire repair program progressed normally in atg7 knockout mice. Finally, autophagic Schwann cells were also found during segmental demyelination in a mouse model of inflammatory peripheral neuropathy. Together, our findings suggest that autophagy is the self-myelin destruction mechanism of Schwann cells, but mechanistically, it is a process distinct from Schwann cell plasticity for nerve repair.


Assuntos
Proteína 7 Relacionada à Autofagia/metabolismo , Autofagia/fisiologia , Doenças Desmielinizantes/etiologia , Bainha de Mielina/patologia , Degeneração Walleriana/complicações , Degeneração Walleriana/patologia , Animais , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Técnicas In Vitro , Lisossomos/patologia , Macrolídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Bainha de Mielina/ultraestrutura , Técnicas de Cultura de Órgãos , Células de Schwann/ultraestrutura , Ciática/genética , Ciática/patologia , Fatores de Tempo , Degeneração Walleriana/genética
9.
Brain Res ; 1627: 143-53, 2015 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-26423936

RESUMO

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-L(E397K), which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L and hNF-L(E397K) mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gait using the Catwalk system. hNF-L(E397K) mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-L(E397K) developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-L(E397K). Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-L(E397K) mice provide a model for determining the efficacy of novel therapies.


Assuntos
Doença de Charcot-Marie-Tooth/fisiopatologia , Transtornos Neurológicos da Marcha/etiologia , Ciática , Animais , Doença de Charcot-Marie-Tooth/genética , Modelos Animais de Doenças , Extremidades/fisiopatologia , Lateralidade Funcional/genética , Humanos , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Locomoção/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Proteínas de Neurofilamentos/genética , Fenótipo , Desempenho Psicomotor/fisiologia , Recuperação de Função Fisiológica/genética , Ciática/complicações , Ciática/etiologia , Ciática/genética
10.
J Neurol ; 262(7): 1673-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25957632

RESUMO

Whole exome sequencing (WES) is a recently developed technique in genetics research that attempts to identify causative mutations in complex, undiagnosed genetic conditions. Causative mutations are usually identified after filtering the hundreds of variants on WES from an individual's DNA selected by the phenotype. We investigated a patient with a slowly progressive chronic axonal distal motor neuropathy and extrapyramidal syndrome using WES, in whom common genetic mutations had been excluded. Variant filtering identified potentially deleterious mutations in three known disease genes: DCTN1, KIF5A and NEFH, which have been all associated with similar clinical presentations of amyotrophic lateral sclerosis, Parkinsonism and/or hereditary spastic paraplegia. Predicting the functional effect of the mutations were analysed in parallel with detailed clinical investigations. This case highlights the difficulties and pitfalls of applying WES in patients with complex neurological diseases and serves as an instructive tale.


Assuntos
Doenças dos Gânglios da Base/complicações , Doenças dos Gânglios da Base/genética , Transtornos dos Movimentos/complicações , Transtornos dos Movimentos/genética , Análise de Sequência de DNA , Idoso , Dor nas Costas/complicações , Progressão da Doença , Complexo Dinactina , Humanos , Cinesina/genética , Masculino , Proteínas Associadas aos Microtúbulos/genética , Mutação/genética , Proteínas de Neurofilamentos/genética , Ciática/complicações , Ciática/genética
11.
Anesth Analg ; 120(6): 1394-404, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25851180

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV)-related painful sensory neuropathies primarily consist of the HIV infection-related distal sensory polyneuropathy and antiretroviral toxic neuropathies. Pharmacotherapy provides only partial relief of pain in patients with HIV/acquired immune deficiency syndrome because little is known about the exact neuropathological mechanisms for HIV-associated neuropathic pain (NP). Hypofunction of γ-aminobutyric acid (GABA) GABAergic inhibitory mechanisms has been reported after peripheral nerve injury. In this study, we tested the hypothesis that HIV gp120 combined with antiretroviral therapy reduces spinal GABAergic inhibitory tone and that restoration of GABAergic inhibitory tone will reduce HIV-related NP in a rat model. METHODS: The application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve plus systemic ddC (one antiretroviral drug) induced mechanical allodynia. The hind paws of rats were inoculated with replication-defective herpes simplex virus (HSV) vectors genetically encoding gad1 gene to express glutamic acid decarboxylase 67 (GAD67), an enzyme that catalyzes the decarboxylation of glutamate to GABA. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The expression of GAD67 in both the lumbar spinal cord and the L4-5 dorsal root ganglia was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging. The immunoreactivity of spinal GABA, pCREB, and pC/EBPß was tested using immunohistochemistry. RESULTS: In the gp120 with ddC-induced neuropathic pain model, GAD67 expression mediated by the HSV vector caused an elevation of mechanical threshold that was apparent on day 3 after vector inoculation. The antiallodynic effect of the single HSV vector inoculation expressing GAD67 lasted >28 days. The area under the time-effect curves in the HSV vector expressing GAD67 was increased compared with that in the control vectors (P = 0.0005). Intrathecal GABA-A/B agonists elevated mechanical threshold in the pain model. The HSV vectors expressing GAD67 reversed the lowered GABA immunoreactivity in the spinal dorsal horn in the neuropathic rats. HSV vectors expressing GAD67 in the neuropathic rats reversed the increased signals of mitochondrial superoxide in the spinal dorsal horn. The vectors expressing GAD67 reversed the upregulated immunoreactivity expression of pCREB and pC/EBPß in the spinal dorsal horn in rats exhibiting NP. CONCLUSIONS: Based on our results, we suggest that GAD67 mediated by HSV vectors acting through the suppression of mitochondrial reactive oxygen species and transcriptional factors in the spinal cord decreases pain in the HIV-related neuropathic pain model, providing preclinical evidence for gene therapy applications in patients with HIV-related pain states.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos , Glutamato Descarboxilase/genética , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/complicações , Nervo Isquiático/enzimologia , Ciática/terapia , Simplexvirus/genética , Zalcitabina , Animais , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Descarboxilação , Modelos Animais de Doenças , Glutamato Descarboxilase/biossíntese , Ácido Glutâmico/metabolismo , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Masculino , Mitocôndrias/metabolismo , Limiar da Dor , Fosforilação , Ratos Sprague-Dawley , Nervo Isquiático/fisiopatologia , Nervo Isquiático/virologia , Ciática/enzimologia , Ciática/genética , Ciática/fisiopatologia , Ciática/virologia , Simplexvirus/enzimologia , Corno Dorsal da Medula Espinal/metabolismo , Superóxidos/metabolismo , Fatores de Tempo , Ácido gama-Aminobutírico/metabolismo
12.
Pain ; 155(1): 93-107, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24041962

RESUMO

Axonal degeneration in peripheral nerves after injury is accompanied by myelin degradation initiated by Schwann cells (SCs). These cells activate autophagy, a ubiquitous cytoprotective process essential for degradation and recycling of cellular constituents. Concomitantly to nerve insult and axonal degeneration, neuropathic pain (NeP) arises. The role of SC autophagy in the mechanisms underlying NeP is still unknown. In this study, we examined the role of the autophagy during the early phase of Wallerian degeneration in NeP induction and chronification by using a murine model of peripheral nerve lesion (chronic constriction injury). We demonstrate that the autophagy inducer rapamycin, administered in the first week after nerve damage, induces long-lasting analgesic and antiinflammatory effects, facilitates nerve regeneration, and prevents pain chronification. Conversely, when autophagy is altered, by means of autophagic inhibitor 3-methyladenine administration or as occurs in activating molecule in Beclin-1-regulated autophagy transgenic mice (Ambra1(+/gt)), NeP is dramatically enhanced and prolonged. Immunohistochemical and ultrastructural evaluations show that rapamycin is able to increase autophagic flux in SCs, to accelerate myelin compaction, and to reduce inflammatory and immune reaction. Proteomic analysis combined with bioinformatic analysis suggests that a redox-sensitive mechanism could be responsible for SC autophagy activation. These data suggest that a deficiency of autophagic activity in SCs can be an early event in the origin of NeP chronification and that autophagy modulation may represent a powerful pharmacological approach to prevent the onset and chronification of NeP in the clinical setting.


Assuntos
Autofagia/fisiologia , Células de Schwann/patologia , Ciática/patologia , Ciática/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Imunossupressores/farmacologia , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Medição da Dor , Células de Schwann/ultraestrutura , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura , Ciática/genética , Sirolimo/farmacologia , Fatores de Tempo
13.
J Neurosci ; 33(13): 5590-602, 2013 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-23536074

RESUMO

Trophic support and myelination of axons by Schwann cells in the PNS are essential for normal nerve function. Herein, we show that deletion of the LDL receptor-related protein-1 (LRP1) gene in Schwann cells (scLRP1(-/-)) induces abnormalities in axon myelination and in ensheathment of axons by nonmyelinating Schwann cells in Remak bundles. These anatomical changes in the PNS were associated with mechanical allodynia, even in the absence of nerve injury. In response to crush injury, sciatic nerves in scLRP1(-/-) mice showed accelerated degeneration and Schwann cell death. Remyelinated axons were evident 20 d after crush injury in control mice, yet were largely absent in scLRP1(-/-) mice. In the partial nerve ligation model, scLRP1(-/-) mice demonstrated significantly increased and sustained mechanical allodynia and loss of motor function. Evidence for central sensitization in pain processing included increased p38MAPK activation and activation of microglia in the spinal cord. These studies identify LRP1 as an essential mediator of normal Schwann cell-axonal interactions and as a pivotal regulator of the Schwann cell response to PNS injury in vivo. Mice in which LRP1 is deficient in Schwann cells represent a model for studying how abnormalities in Schwann cell physiology may facilitate and sustain chronic pain.


Assuntos
Axônios/fisiologia , Axônios/ultraestrutura , Receptores de LDL/metabolismo , Células de Schwann/patologia , Ciática/patologia , Ciática/prevenção & controle , Proteínas Supressoras de Tumor/metabolismo , Actinas/metabolismo , Análise de Variância , Animais , Antígeno CD11b/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Citoplasma/ultraestrutura , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Hiperalgesia/etiologia , Hiperalgesia/genética , Marcação In Situ das Extremidades Cortadas , Indóis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/genética , Proteína Básica da Mielina/metabolismo , Degeneração Neural/etiologia , Degeneração Neural/genética , Medição da Dor , Fosforilação/genética , Células do Corno Posterior/patologia , Células do Corno Posterior/ultraestrutura , Receptores de LDL/deficiência , Proteínas S100/metabolismo , Células de Schwann/ultraestrutura , Ciática/complicações , Ciática/genética , Transtornos das Sensações/etiologia , Medula Espinal/patologia , Proteínas Supressoras de Tumor/deficiência , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Clin J Pain ; 29(11): 967-71, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23370084

RESUMO

OBJECTIVES: Previous studies indicate that genetic variants in genes encoding proteins like matrix metalloproteinase (MMP) enzymes may affect degeneration of the intervertebral disk. One such genetic variant is a single nucleotide polymorphism insertion in the promoter region of the MMP1 gene, that is, the MMP1 rs1799750 2G allele, which increases the MMP1 expression in vitro. In this study, we examined whether the MMP1 rs1799750 2G allele might be associated with disk degeneration and clinical outcome after lumbar disk herniation. MATERIALS AND METHODS: A total of 260 patients with lumbar disk herniation and sciatic pain were included in this study and genotyped for the MMP1 rs1799750 2G allele. RESULTS: The present data showed no differences in the frequency of the MMP1 2G allele in patients recently diagnosed with disk herniation compared with pain-free controls. Moreover, in the patients, the MMP1 2G allele was not directly related to the disk degeneration. However, our data demonstrated that the MMP1 2G allele was associated with both pain and disability, that is, increased visual analog scale score, McGill Pain Questionnaire score, and Oswestry Disability Index score. Clearly, the patients homozygous for the 2G allele had more pain and reduced function compared with those carrying the 1G allele. DISCUSSIONS: Our findings suggest that the MMP1 rs1799750 2G/2G genotype may contribute to low back pain, sciatica, and disability after lumbar disk herniation.


Assuntos
Pessoas com Deficiência , Deslocamento do Disco Intervertebral/genética , Dor Lombar/genética , Vértebras Lombares , Metaloproteinase 1 da Matriz/genética , Polimorfismo de Nucleotídeo Único/genética , Ciática/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Europeu , Feminino , Seguimentos , Estudos de Associação Genética , Genótipo , Humanos , Deslocamento do Disco Intervertebral/complicações , Dor Lombar/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ciática/etiologia , Adulto Jovem
15.
J Neurosci ; 32(29): 9831-4, 2012 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-22815498

RESUMO

Earlier studies have shown that the single nucleotide polymorphism (SNP) A118G (rs1799971) in the opioid receptor mu 1 (OPRM1) gene may affect pain sensitivity. In the present study we investigated whether the A118G SNP could predict clinical outcome regarding progression of pain intensity and disability in patients with low back pain and sciatica after lumbar disc herniation. Patients (n = 258) with lumbar disc herniation and sciatic pain, all European-Caucasian, were recruited from two hospitals in Norway. Pain and disability were rated on a visual analog scale (VAS), by McGill Sensory Questionnaire and by Oswestry Disability Index (ODI) over a 12 months period. The data revealed a significant interaction between sex and A118G genotype regarding the pain intensity during the 12 months (VAS, p = 0.002; McGill, p = 0.021; ODI, p = 0.205, repeated-measures ANOVA). We found that */G women had a slower recovery rate than the */G men. Actually, the */G women had 2.3 times as much pain as the */G men 12 months after the disc herniation (VAS, p = 0.043, one-way ANOVA; p = 0.035, Tukey HSD). In contrast, the A/A women and A/A men seemed to have almost exactly the same recovery rate. The present data suggest that OPRM1 G allele increases the pain intensity in women, but has a protective effect in men the first year after disc herniation.


Assuntos
Deslocamento do Disco Intervertebral/genética , Dor Lombar/genética , Polimorfismo de Nucleotídeo Único , Receptores Opioides mu/genética , Ciática/genética , Adolescente , Adulto , Alelos , Feminino , Seguimentos , Genótipo , Humanos , Deslocamento do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/cirurgia , Dor Lombar/etiologia , Dor Lombar/cirurgia , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Ciática/etiologia , Ciática/cirurgia , Fatores Sexuais , Inquéritos e Questionários
16.
J Neurochem ; 122(5): 976-94, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22697386

RESUMO

A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats, by integrating graded chronic constriction injury (CCI), ipsilateral lumbar dorsal quadrant (iLDQ) and whole blood transcriptomes, and pathway analysis with pain behavior. Correlational bioinformatics identified a range of putative biomarker genes for allodynia intensity, many encoding for proteins with a recognized role in immune/nociceptive mechanisms. A selection of these genes was validated in a separate replication study. Pathway analysis of the iLDQ transcriptome identified Fcγ and Fcε signaling pathways, among others. This study is the first to employ the whole blood transcriptome to identify pain biomarker panels. The novel correlational bioinformatics, developed here, selected such putative biomarkers based on a correlation with pain behavior and formation of signaling pathways with iLDQ genes. Future studies may demonstrate the predictive ability of these biomarker genes across other models and additional variables.


Assuntos
Biomarcadores/metabolismo , Biologia Computacional/métodos , RNA Mensageiro/metabolismo , Ciática/sangue , Ciática/genética , Transcriptoma , Animais , Biologia Computacional/estatística & dados numéricos , Constrição Patológica/complicações , Modelos Animais de Doenças , Lateralidade Funcional , Hiperalgesia/fisiopatologia , Região Lombossacral/patologia , Masculino , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Estimulação Física/efeitos adversos , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores de IgE/genética , Receptores de IgE/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Reprodutibilidade dos Testes , Ciática/etiologia , Transdução de Sinais/genética , Medula Espinal , Estatística como Assunto , Fatores de Tempo
17.
Eur J Pain ; 16(7): 1064-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22337560

RESUMO

BACKGROUND: The COMT enzyme metabolizes catecholamines and thus modulates adrenergic, noradrenergic and dopaminergic signaling. A functional polymorphism in the gene encoding this enzyme, i.e. the COMT Val158Met SNP that reduces enzyme activity, has previously been linked to pain sensitivity. METHODS: We examined if the COMT Val158Met SNP could contribute to discogenic subacute low back pain and sciatica by comparing the frequency of the Val158Met genotypes of degenerative disc disease patients with healthy controls. Moreover, we examined if this SNP could predict the clinical outcome, i.e. the progression of pain and disability. RESULTS: The present data demonstrated that there were no differences in COMT genotype frequencies between the newly diagnosed patients and controls. Analysis of pain and disability in the patients over time revealed, however, a significant or border-line significant increase in McGill sensory score and Oswestry Disability Index (ODI) score for individuals with COMT Met/Met genotype. Furthermore, significant associations between the COMT Met-allele and VAS activity score, McGill sensory score and ODI score were observed in the patients 6 months after inclusion. DISCUSSION: Although the Val158Met SNP was not a risk factor for disc herniation, patients with Met/Met had more pain and slower recovery than those with Val/Met, which in turn also had more pain and slower recovery than those with Val/Val suggesting the SNP contributes to the progression of the symptoms of disc herniation. CONCLUSION: We conclude that the functional COMT Val158Met SNP contributes to long lasting low back pain, sciatica and disability after lumbar disc herniation.


Assuntos
Catecol O-Metiltransferase/genética , Deslocamento do Disco Intervertebral/genética , Dor Lombar/genética , Polimorfismo de Nucleotídeo Único , Ciática/genética , Adolescente , Adulto , Alelos , Avaliação da Deficiência , Discotomia , Feminino , Frequência do Gene , Genótipo , Humanos , Deslocamento do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/cirurgia , Dor Lombar/etiologia , Dor Lombar/cirurgia , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Ciática/etiologia , Ciática/cirurgia , Resultado do Tratamento
18.
J Pain ; 12(3): 370-83, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20889388

RESUMO

UNLABELLED: Cytokines, essential mediators of inflammatory and immune responses, play an important role in the pathophysiological processes associated with neuropathic pain following peripheral nerve injury. Recently, a novel proinflammatory cytokine, the interleukin (IL)-17, was found to orchestrate inflammatory responses in a wide range of inflammatory and autoimmune diseases of the nervous system. Here, we investigated the role of IL-17 in mediating neuroinflammation and pain hypersensitivity using the neuropathic pain model of partial ligation of the sciatic nerve in mice. Compared to wild-type, IL-17 knockout (KO) mice displayed significantly decreased mechanical pain hypersensitivity as well as decreased infiltration of T cells and macrophages to the injured sciatic nerves and the L3-L5 dorsal root ganglia and decreased activation of microglia and astrocytes in the L3-5 dorsal and ventral horns of the spinal cord. Further, intraplantar and intraneural injection of recombinant IL-17 into the hind paw and the sciatic nerve, respectively, induced both mechanical allodynia and thermal hyperalgesia, whereas intrathecal injection produced thermal hyperalgesia. IL-17 administration was associated with a significant increase in the numbers of infiltrating neutrophils and activated dendritic cells in the injected hind paws and infiltrating neutrophils in the injected sciatic nerves. Taken together, our results demonstrate that IL-17 contributes to the regulation of immune cell infiltration and glial activation after peripheral nerve injury and the ensuing neuropathic pain. PERSPECTIVE: IL-17 is an important regulator of immune responses and is involved in inducing and mediating proinflammatory reactions. Using IL-17 KO mice, we have demonstrated that IL-17 contributes to neuroinflammatory responses and pain hypersensitivity following neuropathic injury. This work identifies IL-17 as a potential therapeutic target in neuropathic pain.


Assuntos
Inflamação/metabolismo , Interleucina-17/metabolismo , Ciática/metabolismo , Análise de Variância , Animais , Astrócitos/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Células Dendríticas/patologia , Modelos Animais de Doenças , Gânglios Espinais/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Interleucina-17/administração & dosagem , Interleucina-17/deficiência , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos , Microglia/metabolismo , Neutrófilos/patologia , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Ciática/tratamento farmacológico , Ciática/genética , Ciática/patologia , Células Receptoras Sensoriais/metabolismo , Medula Espinal/patologia , Linfócitos T/metabolismo
19.
Ann Neurol ; 65(2): 218-25, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19259968

RESUMO

OBJECTIVE: Tricyclic antidepressants (TCAs) are one of the first-line pharmacological treatments against neuropathic pain. TCAs increase the extracellular concentrations of noradrenaline and serotonin by blocking the reuptake transporters of these amines. However, the precise downstream mechanism leading to the therapeutic action remains identified. In this work, we evaluated the role of adrenergic receptors (ARs) in the action of TCAs. METHODS: We used pharmacological and genetic approaches in mice to study the role of ARs in the antiallodynic action of the TCA nortriptyline. Peripheral neuropathy was induced by the insertion of a polyethylene cuff around the main branch of the sciatic nerve. The specific role of beta(2)-AR was evaluated by studying beta(2)-AR(-/-) mice. We used von Frey filaments to assess mechanical allodynia. RESULTS: The antiallodynic action of nortriptyline was not affected by cotreatment with the alpha(2)-AR antagonist yohimbine, the beta(1)-AR antagonists atenolol or metoprolol, or the beta(3)-AR antagonist SR 59230A. On the contrary, the beta-AR antagonists propranolol or sotalol, the beta(1)/beta(2)-AR antagonists alprenolol or pindolol, or the specific beta(2)-AR antagonist ICI 118,551 blocked the action of nortriptyline. The effect of nortriptyline was also totally absent in beta(2)-AR-deficient mice. INTERPRETATION: Stimulation of beta(2)-AR is necessary for nortriptyline to exert its antiallodynic action against neuropathic pain. These findings provide new insight into the mechanism by which antidepressants alleviate neuropathic pain. Our results also raise the question of a potential incompatibility between beta-blockers that affect beta(2)-AR and antidepressant drugs in patients treated for neuropathic pain.


Assuntos
Antidepressivos Tricíclicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Receptores Adrenérgicos beta 2/fisiologia , Ciática/tratamento farmacológico , Inibidores da Captação Adrenérgica/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Modelos Animais de Doenças , Hiperalgesia/etiologia , Hiperalgesia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Medição da Dor , Receptores Adrenérgicos beta 2/deficiência , Ciática/complicações , Ciática/genética , Fatores de Tempo
20.
J Neurochem ; 106(2): 640-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18410510

RESUMO

There is increasing evidence that a number of cytokines and their receptors are involved in the processes that lead to the development and maintenance of neuropathic pain states. Here we demonstrate that levels of CX3CR1 (the receptor for the chemokine fractalkine) mRNA in lumbar dorsal root ganglia (DRG) increase 5.8-fold 7 days after sciatic nerve axotomy, and 1.7- and 2.9-fold, 3 and 7 days respectively, after the spared nerve injury (SNI) model of neuropathic pain. In contrast, no significant change in the levels of fractalkine mRNA is apparent in the DRG after axotomy or SNI. The increase in CX3CR1 mRNA is paralleled by a 3.9- and 2.1-fold increase in the number of CX3CR1-positive macrophages in the DRG 7 days after axotomy and SNI, respectively. Expression of CX3CR1 in macrophages is also markedly increased in the sciatic nerve proximal to site of injury, by 25.7-fold after axotomy and 16.2-fold after SNI, 7 days after injury. Intra-neural injection into the sciatic nerve of 400 ng or 100 ng of fractalkine in adult 129OlaHsd mice significantly delayed the development of allodynia for 3 days following SNI. Further, CX3CR1 knockout (KO) mice display an increase in allodynia for three weeks after SNI compared to strain-matched Balb/c controls. Taken together, these results suggest an anti-allodynic role for fractalkine and its receptor in the mouse.


Assuntos
Analgésicos/administração & dosagem , Quimiocina CX3CL1/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ciática/tratamento farmacológico , Ciática/fisiopatologia , Animais , Comportamento Animal , Receptor 1 de Quimiocina CX3C , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Medição da Dor , Limiar da Dor/fisiologia , RNA Mensageiro/metabolismo , Tempo de Reação/efeitos dos fármacos , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Ciática/genética , Ciática/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Fatores de Tempo
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