Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Dis Model Mech ; 10(10): 1253-1260, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28993312

RESUMO

Levels of matrix metalloproteases (MMPs) can be differentially regulated in response to injury or neurological diseases. For instance, it is known that selective and short-term inhibition of MMP-14, a membrane-type 1 MMP, accelerates axon regeneration. Because axon growth and regeneration is impaired in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder characterized by misfolding and deposition of mutant transthyretin (TTR) in the peripheral nervous system (PNS), we presently investigated the expression levels and the potential role for MMP-14 in this condition. By using cell culture studies, a mouse model of disease and human clinical samples, we observed that MMP-14: (i) is overexpressed in FAP nerves, correlating with TTR deposition; (ii) is upregulated in sciatic nerves from a preclinical transgenic mouse model, increasing with TTR deposition; (iii) levels in the PNS and plasma are rescued upon treatment of mice with anakinra or TTR siRNA, drugs acting over the IL-1 signaling pathway or TTR liver synthesis, respectively; (iv) increases in Schwann cells upon incubation with amyloid-like aggregates; and, finally, (v) is increased in plasma of FAP patients, correlating with disease progression. These results highlight the relevance of MMP-14 in the pathophysiology of FAP, suggesting not only a potential role for this molecule as a novel biomarker for therapy follow up, but also as a new potential therapeutic target.


Assuntos
Neuropatias Amiloides Familiares/enzimologia , Metaloproteinase 14 da Matriz/sangue , Degeneração Neural , Nervo Isquiático/enzimologia , Nervo Sural/enzimologia , Neuropatias Amiloides Familiares/sangue , Neuropatias Amiloides Familiares/patologia , Neuropatias Amiloides Familiares/terapia , Animais , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Indução Enzimática , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Fígado/metabolismo , Metaloproteinase 14 da Matriz/biossíntese , Metaloproteinase 14 da Matriz/genética , Camundongos da Linhagem 129 , Camundongos Transgênicos , Pré-Albumina/genética , Pré-Albumina/metabolismo , Interferência de RNA , Terapêutica com RNAi , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Transdução de Sinais , Nervo Sural/patologia , Fatores de Tempo
2.
J Endocrinol ; 216(1): 1-11, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23086140

RESUMO

Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted liquid chromatography-tandem mass spectrometry (LC/MS/MS) to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve, and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Lepr(db); db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, and lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve, and DRG from diabetic mice. Utilizing LC/electrospray ionization/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids) in db/db tissue, with a proximal-to-distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerves to rely on truncated TCA cycle metabolism in the type 2 diabetes environment.


Assuntos
Ciclo do Ácido Cítrico , Diabetes Mellitus Tipo 2/metabolismo , Neuropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Glicólise , Estresse Oxidativo , Sistema Nervoso Periférico/metabolismo , Aconitato Hidratase/metabolismo , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Neuropatias Diabéticas/enzimologia , Regulação para Baixo , Gânglios Espinais/enzimologia , Gânglios Espinais/metabolismo , Peroxidação de Lipídeos , Masculino , Camundongos , Camundongos Mutantes , Neurônios/enzimologia , Neurônios/metabolismo , Sistema Nervoso Periférico/enzimologia , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Nervo Isquiático/enzimologia , Nervo Isquiático/metabolismo , Nervo Sural/enzimologia , Nervo Sural/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
3.
Brain Res ; 1247: 182-7, 2009 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-18992730

RESUMO

The dorsal root ganglia (DRG) have been identified as the target tissue in diabetic somatosensory neuropathy. It has been reported that, in the chronically diabetic state, DRG sensory neurons may undergo morphological changes. In this study, we examined the effect of zenarestat, an aldose reductase inhibitor, on the morphological derangement of the DRG and the sural nerve of streptozotocin-induced diabetic rats (STZ rats) over a 13-month period. The cell area of the DRG in STZ rats was smaller than that in normal rats. A decrease in fiber size was apparent in the sural nerve of the STZ rats, and the fiber density was greater. These morphological changes were reversed in zenarestat-treated STZ rats. The data suggest that, in peripheral sensory diabetic neuropathy, hyperactivation of the polyol pathway induces abnormalities not only in peripheral nerve fiber, but also in the DRG, which is an aggregate of primary sensory afferent cell bodies.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/enzimologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/enzimologia , Quinazolinas/farmacologia , Aldeído Redutase/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/enzimologia , Axônios/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Gânglios Espinais/patologia , Masculino , Degeneração Neural/tratamento farmacológico , Degeneração Neural/enzimologia , Degeneração Neural/etiologia , Polímeros/metabolismo , Quinazolinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/enzimologia , Células Receptoras Sensoriais/patologia , Nervo Sural/efeitos dos fármacos , Nervo Sural/enzimologia , Nervo Sural/patologia , Resultado do Tratamento , Degeneração Walleriana/tratamento farmacológico , Degeneração Walleriana/enzimologia , Degeneração Walleriana/etiologia
4.
Neurology ; 69(3): 268-74, 2007 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-17636064

RESUMO

BACKGROUND: Abnormalities of endogenous fibrinolysis are linked to diabetic macrovascular disease; whether key vascular endothelial regulatory proteins, such as tissue plasminogen activator (tPA), are altered in diabetic neuropathy microvasculature is unknown. This neuropathologic case: control study investigates the hypothesis that tPA expression is regionally deficient in microvessels in human diabetic neuropathy. METHODS: tPA and von Willebrand factor (vWF), a vascular endothelial cell marker, are detected on vascular endothelium by immunoperoxidase methods with specific antibodies on formalin fixed paraffin embedded sural nerve biopsies from six diabetic and six axonal neuropathy control nerves without vasculopathy. The proportion of microvessels in each nerve region expressing tPA is determined by the ratio of tPA positive vessels/total vWF positive vessels on serial sections. RESULTS: tPA expression is lower in diabetic neuropathy cases compared to controls in all regions, including epineurial (62.4 +/- 8.6% vs 91.0 +/- 1.6%, p < 0.02) and endoneurial microvessels (51.7 +/- 7.1% vs 91.5 +/- 2.9%, p < 0.001). CONCLUSIONS: These results demonstrate a four- to sixfold increase in the number of peripheral nerve microvessels lacking immunodetectable tissue plasminogen activator in the epineurial and endoneurial vessels in diabetes, suggesting that impaired endogenous fibrinolysis might contribute to microvascular ischemia in human diabetic neuropathy.


Assuntos
Neuropatias Diabéticas/enzimologia , Nervo Sural/irrigação sanguínea , Nervo Sural/enzimologia , Ativador de Plasminogênio Tecidual/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/enzimologia , Neuropatias Diabéticas/fisiopatologia , Endotélio Vascular/enzimologia , Humanos , Microcirculação/enzimologia , Microcirculação/fisiopatologia , Nervo Sural/fisiopatologia , Ativador de Plasminogênio Tecidual/biossíntese , Ativador de Plasminogênio Tecidual/deficiência
5.
Cell Mol Biol (Noisy-le-grand) ; 53 Suppl: OL1003-9, 2007 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-18184478

RESUMO

INTRODUCTION: To our knowledge, there is little reference in literature with regards to alpha3-isoform of Na+,K+-ATPase in human peripheral nerves. The aim of this study was to determine the expression of the neuronal alpha3-isoform of Na+,K+-ATPase in human sural nerves from patients with a permanent medullary central nervous system injury. MATERIALS AND METHODS: We studied the immunolocalization of alpha3-isoform of Na+,K+-ATPase using a polyclonal antibody against the amino sequence near the phosphorylation site of the alpha3-isoforms of Na+,K+-ATPase using immunohistochemistry and confocal laser scanning microscopy. An antibody specific for alpha2-isoform of Na+,K+-ATPase was used to label the Schwann cells. RESULTS: Morphometric analysis of longitudinal section of human sural nerves showed that the alpha3-isoform of Na+,K+-ATPase was distributed along the length of axolemma. The myelin sheath of the Schwann cells showed clearly a distribution of alpha3- but not alpha2-isoforms of Na+,K+-ATPase at the level of Schmidt-Lanterman incisures. CONCLUSION: The human sural nerve shows a specific localization of the Na+,K+-ATPase alpha3-isoform in the Schmidt-Lanterman incisures of Schwann cells in addition to its localization in axonal membranes.


Assuntos
Células de Schwann/enzimologia , ATPase Trocadora de Sódio-Potássio/análise , Nervo Sural/enzimologia , Sequência de Aminoácidos , Humanos , Microscopia Confocal , Microscopia de Fluorescência , Modelos Moleculares , Dados de Sequência Molecular , Bainha de Mielina/enzimologia , Conformação Proteica
6.
Rheumatol Int ; 24(5): 255-9, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14598179

RESUMO

The aim of this study was to investigate the expression pattern and cellular source of matrix metalloproteinases (MMP) in vasculitic neuropathy. Matrix metalloproteinases are endopeptidases degrading components of extracellular matrix proteins, and they have been implicated in the pathogenesis of inflammatory demyelination. They are induced by cytokines, secreted by inflammatory cells, and enhance T cell migration. Vasculitic neuropathy occurs as a component of systemic vasculitis or as an isolated angiitis of the peripheral nervous system, and T cell-mediated inflammation is detected in its pathogenesis. Nerve biopsy sections of eight patients with nonsystemic vasculitic neuropathy (NSVN) and four with systemic vasculitic neuropathy were examined for the presence of CD4+, CD8+, and CD68+ cells and immunohistochemically for MMP-2 and MMP-9 expression. Nerve biopsies of eight patients with noninflammatory neuropathy were used as a control group. Semiquantitative polymerase chain reaction analysis was performed to detect MMP-2 and MMP-9 mRNA. The predominant cells were CD8+ and CD68+ T cells. Expression of MMP-9, but not MMP-2, was increased in perivascular inflammatory infiltrate in nerve tissues of vasculitic neuropathy patients. This MMP-9 expression correlated positively with immunostaining of CD8+ T cells. No difference was detected between immunostaining patterns of nonsystemic and systemic vasculitic neuropathies with the antibodies used, except in MMP-9 immunostaining, which was found to be enhanced in NSVN group. Polymerase chain reaction analysis revealed elevated mRNA levels of MMP-9 and MMP-2 compared with controls, but this did not reach statistical significance. Our results imply a pathogenic role for MMP-9 secreted from CD8+ cells in vasculitic neuropathy.


Assuntos
Doenças Desmielinizantes/enzimologia , Metaloproteinases da Matriz/metabolismo , Doenças do Sistema Nervoso Periférico/enzimologia , Linfócitos T/imunologia , Vasculite/enzimologia , Adolescente , Adulto , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Biópsia , Vasos Sanguíneos/enzimologia , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiotaxia de Leucócito/imunologia , Doenças Desmielinizantes/fisiopatologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/genética , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , RNA Mensageiro/metabolismo , Nervo Sural/enzimologia , Nervo Sural/imunologia , Nervo Sural/patologia , Vasculite/imunologia , Vasculite/fisiopatologia
7.
Neurology ; 61(11): 1607-10, 2003 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-14663052

RESUMO

Patients with diabetes mellitus (DM) may develop chronic inflammatory demyelinating polyneuropathy (CIDP), which may be difficult to distinguish from diabetic neuropathy (DNP). Here the authors show that immunoreactivity for matrix metalloproteinase-9 on sural nerve biopsies may help to identify CIDP-DM. In a pilot study on 10 CIDP-DM patients with IV immunoglobulins and tight glycemic control, the CIDP-DM patients had a better outcome than DNP patients treated with tight glycemic control only.


Assuntos
Complicações do Diabetes , Metaloproteinase 9 da Matriz/análise , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Nervo Sural/enzimologia , Adulto , Idoso , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Neuropatias Diabéticas/diagnóstico , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 9 da Matriz/imunologia , Pessoa de Meia-Idade , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Nervo Sural/patologia
8.
Acta Neuropathol ; 105(4): 365-72, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12624790

RESUMO

Matrix metalloproteinases (MMPs) are endoproteases that have been implicated in the pathogenesis of inflammatory and vasculitic neuropathies. In systemic lupus erythematosus (SLE), a peripheral neuropathy is frequently seen that is thought to be caused by ischemic nerve damage due to vasculopathy and/or vasculitis of the nutritional vessels. However, the exact pathomechanisms causing SLE neuropathy are largely unknown. Elevated MMP levels have been reported in the serum of SLE patients. Supposing that altered expression of MMPs may contribute to vessel wall damage in SLE neuropathy, we investigated the expression of MMP-1, -2, -3, -9, -10 and -13, and their tissue inhibitors (TIMP-1 and -2) in sural nerves from 12 SLE patients in comparison to normal controls. All MMPs could be detected within blood vessel walls from SLE nerves, whereas in controls MMP-3 and MMP-9 was not found. TIMP-1 and TIMP-2, on the other hand, were not informative. Generally, small and large nutritional vessels in the epineurium were immunoreactive for MMPs and TIMPs. Mononuclear cells, which expressed MMP-1, - 3, -10, -13, and TIMP-1 were also observed in most of the SLE nerves, mostly around epineurial blood vessels, but only occasionally in controls. This indicates that expression of MMPs in mononuclear cells may be related to leukocyte trafficking through the vessel walls. However, the density of TIMP-positive and MMP-positive inflammatory cells did not correlate with morphometric parameters regarding the severity of the neuropathy. Our findings suggest that especially the up-regulation of MMP-3 and MMP-9 within the vessel walls may be responsible for the vascular damage seen in SLE and the resulting chronic combined axonal and demyelinating type of neuropathy frequently found in SLE.


Assuntos
Metaloproteinases da Matriz/biossíntese , Doenças do Sistema Nervoso Periférico/patologia , Nervo Sural/patologia , Adulto , Idoso , Vasos Sanguíneos/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Leucócitos Mononucleares/enzimologia , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Bainha de Mielina/patologia , Doenças do Sistema Nervoso Periférico/enzimologia , Doenças do Sistema Nervoso Periférico/etiologia , Nervo Sural/irrigação sanguínea , Nervo Sural/enzimologia , Inibidor Tecidual de Metaloproteinase-1/biossíntese , Inibidor Tecidual de Metaloproteinase-2/biossíntese
9.
FASEB J ; 15(13): 2508-14, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11689477

RESUMO

The onset of diabetic neuropathy, a complication of diabetes mellitus, has been linked to poor glycemic control. We tested the hypothesis that the mitogen-activated protein kinases (MAPK) form transducers for the damaging effects of high glucose. In cultures of adult rat sensory neurons, high glucose activated JNK and p38 MAPK but did not result in cell damage. However, oxidative stress activated ERK and p38 MAPKs and resulted in cellular damage. In the dorsal root ganglia of streptozotocin-induced diabetic rats (a model of type I diabetes), ERK and p38 were activated at 8 wk duration, followed by activation of JNK at 12 wk duration. We report activation of JNK and increases in total levels of p38 and JNK in sural nerve of type I and II diabetic patients. These data implicate MAPKs in the etiology of diabetic neuropathy both via direct effects of glucose and via glucose-induced oxidative stress.


Assuntos
Neuropatias Diabéticas/etiologia , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Animais , Butadienos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Neuropatias Diabéticas/enzimologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/enzimologia , Glucose/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Imidazóis/farmacologia , MAP Quinase Quinase 4 , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/enzimologia , Nitrilas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Nervo Sural/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno
10.
Neurology ; 53(1): 62-70, 1999 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-10408538

RESUMO

OBJECTIVE: To determine the expression pattern and cellular source of matrix metalloproteinases (MMPs) in chronic inflammatory demyelinating polyneuropathy (CIDP) and nonsystemic vasculitic neuropathy (NSVN). BACKGROUND: MMPs are endopeptidases involved in tissue destruction and infiltration by immune cells in multiple sclerosis and Guillain-Barré syndrome. Enzyme inhibitors of MMPs attenuate clinical symptoms in corresponding animal models of these diseases. MMP inhibition may therefore be a novel approach for the treatment of CIDP and NSVN. However, the spectrum of MMPs expressed in chronic inflammatory neuropathies has not been established. METHODS: The expression of MMP-2, MMP-3, MMP-7, and MMP-9 in T cells, macrophages, and stromal cells in CIDP, NSVN, and noninflammatory neuropathies (NIN) was quantitated by immunohistochemistry. Results were correlated with clinical and electrophysiologic findings. RESULTS: The production of MMP-2 and MMP-9 is increased in nerve tissue in CIDP and NSVN compared with NIN. T cells are the predominant source of MMP-2 and MMP-9 in CIDP and NSVN, whereas macrophages contribute only to a minor extent. Stromal cells of the perineurium/epineurium are an additional source of MMP-2 in NSVN, but not in CIDP. Expression of MMP-3 and MMP-7 was not detectable in CIDP or NSVN. Expression of MMP-2 and MMP-9 did not correlate with clinical disease activity and electrophysiologic measurements. CONCLUSIONS: The upregulation of MMP-2 and MMP-9 is a specific feature of CIDP and NSVN, and selective inhibitors of these enzymes could be used to prevent inflammatory tissue damage. The similar increase of MMP-2 and MMP-9 in both demyelinating (CIDP) and nondemyelinating (NSVN) neuropathies raises doubts about whether MMPs play a primary role in demyelination.


Assuntos
Doenças Desmielinizantes/enzimologia , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , Doenças do Sistema Nervoso Periférico/enzimologia , Polirradiculoneuropatia/enzimologia , Vasculite/enzimologia , Adulto , Idoso , Doença Crônica , Colagenases/metabolismo , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Feminino , Gelatinases/metabolismo , Regulação Enzimológica da Expressão Gênica , Humanos , Inflamação , Macrófagos/enzimologia , Masculino , Metaloproteinase 2 da Matriz , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 7 da Matriz , Metaloproteinase 9 da Matriz , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Polirradiculoneuropatia/patologia , Polirradiculoneuropatia/fisiopatologia , Células Estromais/enzimologia , Nervo Sural/enzimologia , Nervo Sural/patologia , Linfócitos T/enzimologia , Vasculite/patologia , Vasculite/fisiopatologia
11.
Ann Neurol ; 43(4): 427-34, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9546322

RESUMO

Matrix metalloproteinases (MMPs) are a family of enzymes that may be implicated in the pathogenesis of inflammatory demyelinating disorders such as multiple sclerosis. The present study investigated the expression of 92-kd gelatinase (MMP-9) and five other MMPs in sciatic nerve from Lewis rats with autoimmune experimental neuritis (EAN), an experimental model of the Guillain-Barré syndrome (GBS). Quantitative polymerase chain reaction analysis revealed an up-regulation of MMP-9 mRNA with peak levels concurrent with maximal disease severity. Increased mRNA expression was associated with enhanced enzyme activity, as detected by gelatin zymography. Immunohistochemically, MMP-9 could be localized primarily around blood vessels within the epineurium and endoneurium in diseased but not normal sciatic nerve. Among all other MMPs investigated, mRNA levels of matrilysin (MMP-7) were found to be up-regulated at the peak of the disorder, remaining at high levels throughout the clinical recovery phase of the disease. To apply these findings to human disease, sural nerve biopsies from GBS patients were examined. By using immunohistochemistry, positive immunoreactivity against MMP-9 and MMP-7 was noted and corroborated by demonstrating augmented mRNA expression in comparison with noninflammatory neuropathies. Furthermore, increased MMP-9 activity was detected by zymography. These findings indicate that 92-kd gelatinase and matrilysin are selectively up-regulated during EAN and expressed in nerves of GBS patients and thus may contribute to the pathogenesis of inflammatory demyelination of the peripheral nervous system.


Assuntos
Colagenases/biossíntese , Regulação Enzimológica da Expressão Gênica , Metaloendopeptidases/biossíntese , Neurite Autoimune Experimental/enzimologia , Polirradiculoneuropatia/enzimologia , Nervo Isquiático/enzimologia , Nervo Sural/enzimologia , Animais , Biópsia , Feminino , Humanos , Metaloproteinase 7 da Matriz , Metaloproteinase 9 da Matriz , Neurite Autoimune Experimental/patologia , Neurite Autoimune Experimental/fisiopatologia , Reação em Cadeia da Polimerase , Polirradiculoneuropatia/patologia , Polirradiculoneuropatia/fisiopatologia , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos Lew , Nervo Sural/patologia , Fatores de Tempo , Transcrição Gênica
12.
Acta Neuropathol ; 93(6): 628-32, 1997 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9194903

RESUMO

We report a case late infantile neuronal ceroid lipofuscinosis (NCL). Abnormal granules were found in the skeletal muscle fibers, Schwann cells, perineurial cells, endothelial cells, fibroblasts, and perivascular smooth muscle cells in the sural nerve. Electron microscopy revealed that these granules showed fingerprint profiles, curvilinear profiles or membrane-bound membranous structures. Acid phosphatase reaction was increased in these cells. Immunohistochemical studies for mitochondrial ATP synthase subunit c showed a strong reaction in these cells, suggesting abnormal accumulation of subunit c. Immunohistochemistry for subunit c in muscle may be useful in the diagnosis of late infantile NCL.


Assuntos
Mitocôndrias Musculares/enzimologia , Músculo Esquelético/enzimologia , Lipofuscinoses Ceroides Neuronais/enzimologia , ATPases Translocadoras de Prótons/metabolismo , Adulto , Grânulos Citoplasmáticos/enzimologia , Grânulos Citoplasmáticos/patologia , Grânulos Citoplasmáticos/ultraestrutura , Feminino , Humanos , Imuno-Histoquímica , Mitocôndrias Musculares/patologia , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Lipofuscinoses Ceroides Neuronais/patologia , Nervo Sural/enzimologia , Nervo Sural/patologia , Nervo Sural/ultraestrutura
13.
J Auton Nerv Syst ; 67(1-2): 105-8, 1997 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-9470150

RESUMO

Paleopathology is a well established science with numerous papers and books on the subject but, in contrast, paleoneurobiology is almost non-existent. We examined sections of sural nerves obtained from seven embalmed Egyptian mummies and one naturally desiccated Peruvian mummy, immunohistochemically stained for several neurochemicals. Immunoreactivity for type I nitric oxide synthase (NOS), protein gene-product 9.5, galanin, and calcitonin gene-related peptide immunoreactivity was observed in the nervi nervorum. No immunoreactivity was seen using antibodies directed against substance P, vasoactive intestinal polypeptide or neuropeptide Y. NOS-immunoreactivity was also observed in biopsied samples of contemporaneous human sural nerves. Thus, using a standard immunohistochemical technique it was possible to detect neurochemicals in ancient sural nerves that had been preserved by mummification. Furthermore, the finding of NOS in the ancient nerves led to its detection in contemporaneous sural nerves.


Assuntos
Múmias , Neuropeptídeos/metabolismo , Óxido Nítrico Sintase/metabolismo , Nervo Sural/metabolismo , Egito , Humanos , Imuno-Histoquímica , Nervo Sural/enzimologia
14.
J Neurol Sci ; 135(1): 51-4, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8926496

RESUMO

The genotype for N-acetyltransferase was analyzed in five Japanese patients with isoniazid neuropathy by using the allele specific polymerase chain reaction for a single slice of the 30-year-old paraffin-embedded and hematoxylin-eosin stained sural nerve biopsy specimens. We found slow acetylator genotypes for N-acetyltransferase in all isoniazid neuropathy patients. This result confirmed that patients with the slow acetylator genotype tend to develop neuropathy after administration of isoniazid.


Assuntos
Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/metabolismo , Isoniazida/efeitos adversos , Doenças do Sistema Nervoso Periférico/genética , Nervo Sural/enzimologia , Acetilação/efeitos dos fármacos , Alelos , Arilamina N-Acetiltransferase/genética , Sequência de Bases , Biópsia , Primers do DNA/genética , Amarelo de Eosina-(YS) , Genótipo , Hematoxilina , Humanos , Mutação/fisiologia , Inclusão em Parafina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/enzimologia , Reação em Cadeia da Polimerase , Nervo Sural/fisiopatologia , Fatores de Tempo
15.
Cardiology ; 85(3-4): 145-53, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7987869

RESUMO

A case of severe cardiac involvement is reported in a patient affected with familial amyloidotic polyneuropathy due to the Portuguese type I variant (Val-->Met30) of the transthyretin (prealbumin) molecule. Echocardiographic and hemodynamic studies suggested the presence of a progressive infiltrative cardiomyopathy that was later confirmed by endomyocardial biopsy. Amyloid deposits were found in both intra- and extra-myofiber location and thought to be related to primary involvement of the heart. Norepinephrine content of myocardial bioptic specimens was about threefold lower than normal, indicating that autonomic denervation may contribute to the maintenance and progression of cardiomyopathy. A sample obtained from the sural nerve showed a loss of myelinated fibers along with accumulation of amyloid masses in the endoneurial space. This histopathologic pattern correlated with a sharp decrease in the activity of the enzyme subserving electrochemical conduction through the axonal membrane, Na+, K(+)-ATPase.


Assuntos
Neuropatias Amiloides/metabolismo , Amiloide/metabolismo , Miocárdio/metabolismo , Pré-Albumina/metabolismo , Neuropatias Amiloides/complicações , Neuropatias Amiloides/genética , Neuropatias Amiloides/patologia , Amiloidose/genética , Amiloidose/metabolismo , Amiloidose/patologia , Cardiomiopatias/complicações , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Norepinefrina/análise , ATPase Trocadora de Sódio-Potássio/análise , Nervo Sural/enzimologia , Nervo Sural/patologia
16.
Funct Neurol ; 8(1): 33-42, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8330752

RESUMO

Conversion of glucose to fructose via sorbitol depends upon the enzymes aldose reductase and sorbitol dehydrogenase and is called the polyol pathway. It is particularly active in muscle from patients with X-linked muscular dystrophies (15). This investigation shows enhanced metabolism of glucose to fructose in muscle from patients with ALS. Evidence is also presented showing increased activities of ketohexokinase and F-1-P splitting aldolase, which suggests that further metabolism of fructose may occur via a fructolytic pathway. Investigation of protein glycation, by an adapted fructosamine assay, in post mortem muscle, sural nerve and blood indicates that there is an increased concentration of glucose in muscle and nerve in the period prior to sampling, but blood glucose concentrations were within normal limits. The implications of fructolysis and the relationship of altered glucose metabolism in ALS are discussed.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Frutose/metabolismo , Glucose/metabolismo , Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/fisiopatologia , Autopsia , Feminino , Frutoquinases/metabolismo , Glicosilação , Humanos , L-Iditol 2-Desidrogenase/metabolismo , Masculino , Músculos/enzimologia , Músculos/metabolismo , Proteínas/metabolismo , Nervo Sural/enzimologia , Nervo Sural/metabolismo
17.
Acta Neuropathol ; 85(4): 419-30, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-7683169

RESUMO

Polyglucosan body diseases in adults, contrary to infantile cases (Andersen's disease or type IV glycogenosis or amylopectinosis), are usually not associated with a significant deficiency of the branching enzyme (= amylo-1,4-1,6 transglucosidase). We, therefore, report on a 19-year-old male with complete branching enzyme deficiency presenting with severe myopathy, dilative cardiomyopathy, heart failure, dysmorphic features, and subclinical neuropathy. His 14-year-old brother had similar symptoms and was erroneously classified by a previous muscle biopsy as having central core disease but could later be identified as also having polyglucosan body myopathy. The skeletal muscle, endomyocardiac, and sural nerve biopsies as well as the autopsy revealed extraordinarily severe deposits of polyglucosan bodies not only in striated and smooth muscle fibers, but also in histiocytes, fibroblasts, perineurial cells, axons and astrocytes. Occasional paracrystalline mitochondrial inclusions were also noted. Thus, this patient represents to our knowledge the first juvenile, familial case of polyglucosan body disease with total branching enzyme deficiency and extensive polyglucosan body storage.


Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/deficiência , Doença de Depósito de Glicogênio Tipo IV/patologia , Doenças Musculares/patologia , Adolescente , Adulto , Humanos , Fígado/enzimologia , Masculino , Músculos/enzimologia , Músculos/patologia , Miocárdio/patologia , Pele/enzimologia , Coloração e Rotulagem , Nervo Sural/enzimologia , Nervo Sural/patologia
18.
Rinsho Shinkeigaku ; 32(2): 199-202, 1992 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-1377106

RESUMO

A 30-year-old man had an acute onset of orthostatic lightheadedness, sweating disturbance, paroxysmal cough and loss of potency. These symptoms reached the peak in two weeks, and then remitted very slowly. He was admitted to our hospital for further evaluation when he was 39 years old. Neurological examinations revealed right Horner's syndrome, dry skin and impotence, but neither motor nor sensory system was impaired. No abnormalities were found on routine examinations of the blood and cerebrospinal fluid, motor and sensory nerve velocities, computed tomography and electroencephalography. On sural nerve biopsy, the density of unmyelinated fibers was mildly decreased (13,857/mm2), whereas that of myelinated fibers was normal (7,220/mm2). Autonomic function tests disclosed orthostatic hypotension (-31 mmHg) on tilting, reduced levels of serum noradrenaline and vanillyl mandelic acid, supersensitive responses to noradrenaline infusion and adrenaline eye-dripping, severe sweating impairment and complete absence of sympathetic skin response. On the other hand, Aschner's test, Czermak's test and coefficient variation of R-R intervals were all normal. These results suggested that the chief lesion was located in the postganglionic fiber of sympathetic efferent pathway. We (Hayashi et al, 1990) quantified acetylcholinesterase (AchE)-positive fibers in the specimens of sural nerve biopsy, and reported that the density of AchE-positive fibers was correlated to the function of sympathetic postganglionic fibers. The density of AchE-positive fibers in the present case of acute idiopathic pandysautonomia (AIPD) was severely decreased to 225/mm2 by optical microscopy (control: 5,703 +/- 1,289/mm2), and to 2,996/mm2 by electron microscopy (control: 14,112 +/- 3,987/mm2).(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Acetilcolinesterase/metabolismo , Doenças do Sistema Nervoso Autônomo/enzimologia , Nervo Sural/enzimologia , Doença Aguda , Adulto , Doenças do Sistema Nervoso Autônomo/patologia , Histocitoquímica , Humanos , Masculino , Coloração e Rotulagem
19.
Acta Neuropathol ; 82(4): 316-20, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1662002

RESUMO

A detailed morphometric study was performed on sural nerve biopsies to determine the consistency of sensory nerve pathology in amyotrophic lateral sclerosis (ALS) and to seek a correlation between the severity of peripheral nerve pathology and disease duration. Nerve biopsies from patients with ALS consistently showed evidence of early axonal atrophy, increased remyelination and a shift in the diameter distributions curve towards smaller fiber diameters. Importantly, the severity of sensory nerve pathology in ALS patients correlated with disease duration. The peripheral nerve sodium pump concentration of patients was not reduced. It is concluded that an ingravescent dorsal root ganglion neuronopathy is seen in the incipient stages of ALS, preferentially affecting the largest neurons and resulting in turn in progressive axonal atrophy, secondary demyelination-remyelination and finally in nerve fiber degeneration. Etiologically, a parallel involvement of motor and sensory neurons suggests a more widespread metabolic disturbance in ALS than simply "sick" motor neurons.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Neurônios Aferentes/patologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/enzimologia , Sítios de Ligação/efeitos dos fármacos , Feminino , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Bainha de Mielina/ultraestrutura , Neurônios Aferentes/enzimologia , Ouabaína/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Nervo Sural/enzimologia , Nervo Sural/metabolismo , Nervo Sural/ultraestrutura
20.
Int J Lepr Other Mycobact Dis ; 53(2): 238-46, 1985 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-4020211

RESUMO

Using the immunoperoxidase staining method, tissue muramidase (lysozyme) activity was studied in 34 nerve biopsies from leprosy patients and compared to findings in the skin. In a majority of lepromatous and borderline-lepromatous leprosy patients, the enzyme was seen to form a saccular pattern within the cells; whereas a granular pattern was found at the tuberculoid end of the leprosy spectrum, as well as during reversal reactions. Indeed, the most intense enzymatic activity was found in four patients with reversal reactions. Compared to the skin, muramidase activity was found to be more intense and persisted longer in the nerves. Successful antileprosy treatment reduced the enzymatic activity in both the nerves and the skin, but more so in the skin. Schwann cells and axons did not show muramidase activity, indicating that the muramidase-positive cells are not of neuronal origin. Our results suggest that a high percentage of mononuclear cells infiltrating the peripheral nerves in leprosy are derived from blood monocytes. The function of tissue muramidase in leprosy is not yet clear. Its peculiar intracellular distribution pattern in the different forms of leprosy, however, warrants further study to elucidate its role in the pathogenesis of the disease.


Assuntos
Hanseníase/enzimologia , Muramidase/análise , Adolescente , Adulto , Dapsona/uso terapêutico , Feminino , Humanos , Hanseníase/tratamento farmacológico , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Nervo Radial/enzimologia , Nervo Sural/enzimologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...