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1.
Adv Exp Med Biol ; 1190: 357-369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760656

RESUMO

A large variety of drugs have been reported to cause peripheral neuropathies as dose-limiting adverse effects; however, most of them primarily affect axons and/or neuronal cell bodies rather than Schwann cells and/or myelin sheaths. In this chapter, we focus on the drugs that seem to elicit the neuropathies with schwannopathy and/or myelinopathy-predominant phenotypes, such as amiodarone, dichloroacetate, and tumor necrosis factor-α antagonists. Although the pathogenesis of demyelination induced by these drugs remain largely obscure, the recent in vivo and in vitro studies have implicated the involvement of metabolic abnormalities and impaired autophagy in Schwann cells and immune system disorders in the disruption of neuron-Schwann cell contact and interactions.


Assuntos
Doenças Desmielinizantes/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Bainha de Mielina/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Células de Schwann/patologia , Amiodarona/efeitos adversos , Axônios , Ácido Dicloroacético/efeitos adversos , Humanos , Bainha de Mielina/efeitos dos fármacos , Células de Schwann/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
2.
Life Sci ; 237: 116954, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610192

RESUMO

Sirt3 enzyme and mitochondrial abnormality can be related to excess fatigue or muscular dysfunction in multiple sclerosis (MS).Ellagic acid (EA) has a mitochondrial protector, iron chelator, antioxidant, and axon regenerator in neurons.In this study the effect of EAon muscle dysfunction, its mitochondria, and Sirt3 enzyme incuprizone-induced model of MSwas examined. Demyelination was induced by a diet containing 0.2% w/w cuprizone (Cup) for 42 days and EA administered daily (5, 50, and 100 mg/kg P.O) either with or without cuprizone in mice. Behavioral tests were assessed, and muscle tissue markers ofoxidative stress, mitochondrial parameters, mitochondrial respiratory chain activity, the Sirt3 protein level, and Sirt3 expression were also determined. Luxol fast blue staining and the behavioral tests were performed toassess the implemented model. In Cup group an increased oxidative stress in their muscle tissues was observed. Also, muscle mitochondria exhibited mitochondria dysfunction, lowered mitochondrial respiratory chain activity, Sirt3 protein level, and Sirt3 expression.EA prevented most of these anomalous alterations. Sub-chronicEA co-treatment dose-dependently ameliorated behavioral and muscular impairment in mice that received Cup.EA can effectively protect muscle tissue against cuprizone-induced demeylination via the mitochondrial protection, oxidative stress prevention and Sirt3 overexpression.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cuprizona/toxicidade , Doenças Desmielinizantes/tratamento farmacológico , Ácido Elágico/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Doenças Musculares/prevenção & controle , Sirtuína 3/metabolismo , Animais , Quelantes/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Estresse Oxidativo/efeitos dos fármacos
4.
Adv Gerontol ; 32(3): 338-346, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31512419

RESUMO

The followings were estimated in the 3-5 and 15-17 months 129/Sv cuprizone- and melatonin-treated mice: the number of activated T-lymphocytes, macrophages, neural stem cells (determined by CD3+, Mac1+ and nestin+ markers), the structurally unchanged neurons, the malondialdehyde (MDA) content and the antioxidant enzyme activities in the brain; the blood thymus hormone thymulin level; and the behavioural indices. The mice were fed with cuprizone for 3 weeks. From the 8th day of the cuprizone treatment the mice were injected with melatonin (1 mg/kg, at 18:00 daily). As a result, the number of the CD3+-, Mac1+-, and nestin+-cells and the MDA content increased while the glutathione peroxidise (GP) activity decreased in the brain of young and aged mice under the influence of cuprizone. In mice of both age groups the proportion of unchanged neurons in the central nervous system, motor and emotional activity and muscle tone were decreased. Regardless of the age of the mice the injections of melatonin decrease the number of СD3+, Мас1+-cells, content of MDA, increase activity of GP and thymulin level. Decrease of the number of nestin+-cells coincides with the growth of the number of unchanged neurons. The effect of both neurotoxin and melatonin on immune factors, the structure and functional state of neurons was more pronounced in young mice. Thus, the positive effect of melatonin in young and aged mice with the cuprizone-induced demyelination was realized mainly through the pathogenetic factors of pathology.


Assuntos
Doenças Desmielinizantes , Melatonina , Neurônios , Animais , Antioxidantes/farmacologia , Cuprizona , Doenças Desmielinizantes/induzido quimicamente , Modelos Animais de Doenças , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos
5.
Neurochem Res ; 44(9): 2170-2181, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31420834

RESUMO

Acute inhalation of combustion smoke produces long-term neurologic deficits in survivors. To study the mechanisms that contribute to the development of neurologic deficits and identify targets for prevention, we developed a mouse model of acute inhalation of combustion smoke, which supports longitudinal investigation of mechanisms that underlie the smoke induced inimical sequelae in the brain. Using a transgenic mouse engineered to overexpress neuroglobin, a neuroprotective oxygen-binding globin protein, we previously demonstrated that elevated neuroglobin preserves mitochondrial respiration and attenuates formation of oxidative DNA damage in the mouse brain after smoke exposure. In the current study, we show that elevated neuronal neuroglobin attenuates the persistent inflammatory changes induced by smoke exposure in the mouse brain and mitigates concordant smoke-induced long-term neurobehavioral deficits. Specifically, we found that increases in hippocampal density of GFAP and Iba-1 positive cells that are detected post-smoke in wild-type mice are absent in the neuroglobin overexpressing transgenic (Ngb-tg) mice. Similarly, the smoke induced hippocampal myelin depletion is not observed in the Ngb-tg mice. Importantly, elevated neuroglobin alleviates behavioral and memory deficits that develop after acute smoke inhalation in the wild-type mice. Taken together, our findings suggest that the protective effects exerted by neuroglobin in the brains of smoke exposed mice afford protection from long-term neurologic sequelae of acute inhalation of combustion smoke. Our transgenic mouse provides a tool for assessing the potential of elevated neuroglobin as possible strategy for management of smoke inhalation injury.


Assuntos
Hipocampo/metabolismo , Inflamação/metabolismo , Neuroglobina/metabolismo , Animais , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Inflamação/induzido quimicamente , Aprendizagem/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neuroglobina/genética , RNA Mensageiro/metabolismo , Fumaça
6.
Int Immunopharmacol ; 75: 105819, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31421546

RESUMO

Although several therapies are approved, none promote re-myelination in multiple sclerosis (MS) patients, limiting their ability for sustained recovery. Thus, treatment development in MS has the opportunity to tackle the challenges, including experimental therapies targeting neuroprotection and re-myelination. Here, we provide a novel therapeutic target for Ginkgolide K (GK) that is now becoming a very critical natural compound to treat demyelination and neurodegeneration. GK improves behavioral dysfunction and demyelination in cuprizone (CPZ) model, followed by the migration and enrichment of astrocytes in the corpus callosum. Both in vitro and in vivo experiments demonstrates that GK triggers the upregulation of Nrf2/HO-1 in astrocytes and inhibition of p-NF-kB/p65, which is associated with the outcome of anti-inflammation and anti-oxidation by suppressing the production of IL-6 and TNFα as well as nitric oxide and iNOS in astrocytes. Further findings suggest that IGF/PI3K, but not BDNF, was induced in the corpus callosum after GK treatment, revealing that Nrf2 activation inhibited caspase-3 and apoptosis in O4+ oligodendrocytes possibly through IGF/PI3K signaling molecules. Since the current immunomodulatory therapies for MS have failed to prevent patients from entering the progressive phase of the disease, thus targeting Nrf2 in astrocytes with GK would be an ideal strategy for myelin protection and regeneration.


Assuntos
Astrócitos/efeitos dos fármacos , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Bainha de Mielina/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Somatomedinas/metabolismo , Animais , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Cuprizona , Citocinas/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/metabolismo , Ginkgolídeos/uso terapêutico , Lactonas/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL
7.
J Neuroinflammation ; 16(1): 165, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399117

RESUMO

BACKGROUND: The association of gut microbiota and diseases of the central nervous system (CNS), including multiple sclerosis (MS), has attracted much attention. Although a previous analysis of MS gut microbiota revealed a reduction in species producing short-chain fatty acids (SCFAs), the influence of these metabolites on demyelination and remyelination, the critical factors of MS pathogenesis, remains unclear. METHODS: To investigate the relationship between demyelination and gut microbiota, we administered a mixture of non-absorbing antibiotics or SCFAs to mice with cuprizone-induced demyelination and evaluated demyelination and the accumulation of microglia. To analyze the direct effect of SCFAs on demyelination or remyelination, we induced demyelination in an organotypic cerebellar slice culture using lysolecithin and analyzed the demyelination and maturation of oligodendrocyte precursor cells with or without SCFA treatment. RESULTS: The oral administration of antibiotics significantly enhanced cuprizone-induced demyelination. The oral administration of butyrate significantly ameliorated demyelination, even though the accumulation of microglia into demyelinated lesions was not affected. Furthermore, we showed that butyrate treatment significantly suppressed lysolecithin-induced demyelination and enhanced remyelination in an organotypic slice culture in the presence or absence of microglia, suggesting that butyrate may affect oligodendrocytes directly. Butyrate treatment facilitated the differentiation of immature oligodendrocytes. CONCLUSIONS: We revealed that treatment with butyrate suppressed demyelination and enhanced remyelination in an organotypic slice culture in association with facilitating oligodendrocyte differentiation. Our findings shed light on a novel mechanism of interaction between the metabolites of gut microbiota and the CNS and may provide a strategy to control demyelination and remyelination in MS.


Assuntos
Butiratos/uso terapêutico , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/prevenção & controle , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Remielinização/efeitos dos fármacos , Animais , Antibacterianos/toxicidade , Butiratos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Técnicas de Cultura de Órgãos , Remielinização/fisiologia
8.
Int Immunopharmacol ; 75: 105777, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31357085

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelination disease characterized by autoimmune damage to the central nervous system. In this disease, failure of remyelination could cause persistent disability. Cordycepin, also known as 3'-deoxyadenosine, exerts anti-inflammatory, anti-oxidic, anti-apoptotic and neuroprotective effects. The cuprizone (CPZ) model has been widely used to study MS as it mimics some characteristics of demyelination disease. To determine whether cordycepin promotes remyelination and functional recovery after CPZ-induced demyelination, we administered cordycepin to the CPZ-induced demyelination mice. Cordycepin reversed CPZ-induced loss of body weight and rescued motor dysfunction in the model mice. Cordycepin effectively promoted remyelination and enhanced MBP expression in the corpus callosum. Cordycepin also inhibited the CPZ-induced increase in the number of Iba1-positive microglia, GFAP-positive astrocytes and Olig2-positive oligodendroglial precursor cells in the corpus callosum and cerebral cortex. Pro-inflammatory cytokine expression (IL-1ß and IL-6) was inhibited while anti-inflammatory cytokine IL-4 and neurotrophic factor BDNF release was elevated in the corpus callosum and hippocampus after cordycepin treatment. In addition, we also found that cordycepin ameliorated CPZ-induced body weight loss, motor dysfunction, demyelination, glial cells activation and pro-inflammatory cytokine expression in the corpus callosum and hippocampus. Our results suggest that cordycepin may represent a useful therapeutic agent in demyelination-related diseases via suppression of neuroinflammation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Desoxiadenosinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Remielinização/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/imunologia , Cuprizona , Citocinas/imunologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/imunologia , Desoxiadenosinas/farmacologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia
9.
Nat Neurosci ; 22(7): 1046-1052, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182869

RESUMO

Failed regeneration of CNS myelin contributes to clinical decline in neuroinflammatory and neurodegenerative diseases, for which there is an unmet therapeutic need. Here we reveal that efficient remyelination requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state. We propose that impaired microglia death and/or repopulation may underpin dysregulated microglia activation in neurological diseases, and we reveal therapeutic targets to promote white matter regeneration.


Assuntos
Doenças Desmielinizantes/fisiopatologia , Microglia/fisiologia , Regeneração Nervosa/fisiologia , Animais , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Doenças Desmielinizantes/induzido quimicamente , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação , Lisofosfatidilcolinas/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/classificação , Esclerose Múltipla/patologia , Necrose , Nestina/análise , Fagocitose , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA , Substância Branca/fisiologia
10.
Elife ; 82019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31071011

RESUMO

Oligodendrocyte maturation is necessary for functional regeneration in the CNS; however, the mechanisms by which the systemic environment regulates oligodendrocyte maturation is unclear. We found that Transforming growth factor (TGF)-ß1, which is present in higher levels in the systemic environment, promotes oligodendrocyte maturation. Oligodendrocyte maturation was enhanced by adult mouse serum treatment via TGF-ß type I receptor. Decrease in circulating TGF-ß1 level prevented remyelination in the spinal cord after toxin-induced demyelination. TGF-ß1 administration promoted remyelination and restored neurological function in a multiple sclerosis animal model. Furthermore, TGF-ß1 treatment stimulated human oligodendrocyte maturation. These data provide the therapeutic possibility of TGF-ß for demyelinating diseases.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Doenças Desmielinizantes/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Oligodendroglia/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Fator de Crescimento Transformador beta1/administração & dosagem , Adulto , Animais , Células Cultivadas , Doenças Desmielinizantes/induzido quimicamente , Modelos Animais de Doenças , Humanos , Camundongos , Fator de Crescimento Transformador beta1/sangue , Resultado do Tratamento
11.
Mol Neurobiol ; 56(10): 6873-6882, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30937636

RESUMO

White matter (WM) abnormalities are a well-established feature of Huntington disease (HD), although their nature is not fully understood. Here, we asked whether remyelination as a measure of WM plasticity is impaired in a model of HD. Using the cuprizone assay, we examined demyelination and remyelination responses in YAC128 HD mice. Treatment with 0.2% cuprizone (CPZ) for 6 weeks resulted in significant reduction in mature (GSTπ-positive) oligodendrocyte counts and FluoroMyelin staining in the corpus callosum, leading to similar demyelination states in YAC128 and wild-type (WT) mice. Six weeks following cessation of CPZ, we observed robust remyelination in WT mice as indicated by an increase in mature oligodendrocyte counts and FluoroMyelin staining. In contrast, YAC128 mice exhibited an impaired remyelination response. The increase in mature oligodendrocyte counts in YAC128 HD mice following CPZ cessation was lower than that of WT. Furthermore, there was no increase in FluoroMyelin staining compared to the demyelinated state in YAC128 mice. We confirmed these findings using electron microscopy where the CPZ-induced reduction in myelinated axons was reversed following CPZ cessation in WT but not YAC128 mice. Our findings demonstrate that remyelination is impaired in YAC128 mice and suggest that WM plasticity may be compromised in HD.


Assuntos
Doença de Huntington/fisiopatologia , Remielinização/fisiologia , Animais , Axônios/patologia , Axônios/ultraestrutura , Corpo Caloso/patologia , Corpo Caloso/fisiopatologia , Cuprizona , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Humanos , Doença de Huntington/complicações , Doença de Huntington/patologia , Masculino , Camundongos Transgênicos , Neuroglia/metabolismo , Neuroglia/patologia
12.
Neurochem Int ; 126: 229-238, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30940543

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). In MS, a long disease duration is known to be a strong risk factor for converting the clinical course of the disease from relapse remitting MS to secondary progressing MS. There is a hypothesis that long sustained demyelination may exhaust neurons, however, pathological changes induced in neurons following demyelination remain unknown. Cuprizone administration can induce and sustain demyelination in the mouse CNS. We examined pathological changes in mice following long sustained demyelination caused by up to 34-week cuprizone administration. Twelve-week cuprizone administration induced severe demyelination in the cerebral cortex, corpus callosum and deep cerebellar nuclei. Demyelination persisted up to 34 weeks, as shown by myelin basic protein immunohistochemistry. In contrast, cuprizone administration developed demyelination in the striatum by week 34. In these demyelinated regions, no neuronal loss was observed. However, in the striatum and deep cerebellar nuclei, cuprizone-induced demyelination changed the intracellular distribution of parvalbumin (PV). Furthermore, in the striatum, there was an increase in PV in the demyelinated axons and most PV immunoreactivity did not co-localize with SMI32 immunoreactivity in mice with 34-week cuprizone administration. Further, mice with 34-week cuprizone administration showed motor coordination dysfunction in the balance beam test. However, 12-week withdrawal from the cuprizone diet induced remyelination in the regions and motor coordination dysfunction recovered. These results indicate that 34-week cuprizone administration induces and sustains demyelination and results in reversible motor coordination dysfunction. The change of intracellular PV distribution suggests that PV may protect demyelinated axons by Ca2+ buffering. This model may be useful to investigate pathological and behavioral changes following demyelination in the CNS.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Quelantes/toxicidade , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Animais , Esquema de Medicação , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Tempo
13.
Neuropeptides ; 75: 75-84, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31030907

RESUMO

Mesenchymal stem cells (MSCs) have a notable potential to modulate immune responses and protect the central nervous system (CNS), mostly by secreting factors that affect inflammation. MSCs have the ability to improve several autoimmune diseases in animal models including multiple sclerosis (MS). MS is a disease of the CNS among adult humans and it is characterized by demyelination, neuroinflammation and gliosis. In this study, we first induced chronic demyelination by cuprizone, followed by intraventricular injection of MSC. Our results showed that MSC significantly decreased microgliosis and astrocytosis by secreting cytokines that have neuroprotective activity including TGF-ß and CX3CL1. Also, downregulation of IL-1ß and TNF-α as inflammatory chemokines was seen along with decreased astrocytes and microglia activation. Finally, these results showed that trophic factors secreted by MSC can increase oligodendrocyte population and remyelination rate by reducing pro-inflammatory factors. These findings demonstrate that MSC could decrease inflammation, gliosis and demyelination with neuroprotective and immunomodulating properties in chronic cuprizone demyelination model. Therefore MSC transplantation can be considered as a suitable approach for enhancing myelination and reducing inflammation in diseases such as MS.


Assuntos
Doenças Desmielinizantes/metabolismo , Células-Tronco Mesenquimais , Neuroglia/metabolismo , Animais , Quimiocina CX3CL1/metabolismo , Cuprizona , Citocinas/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Masculino , Camundongos , Fator de Crescimento Transformador beta/metabolismo
14.
J Mol Histol ; 50(3): 263-271, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016544

RESUMO

Oxidative stress with mitochondrial defects has a central role in the development and deterioration of Multiple sclerosis (MS). According to new findings of the effects of metformin on mitochondrial function, has attracted a lot of attention. Furthermore, it is suggested that metformin exerts its beneficial influence through AMP-activated protein kinase (AMPK) pathway. In the current study, we investigated the possible protective effects of metformin on oxidative stress and mitochondrial function by activating the AMPK pathway in the cuprizone-induced demyelination. Mice were fed with cuprizone for 6 weeks. Animals simultaneously received metformin. After sacrificing animals, myelinations, and gliosis, changes in transcription factor and biochemical analysis were assessed. Transmission electron microscopy and luxol fast blue staining revealed that the myelinated axons within corpus callosum of cuprizone-induced demyelination animals increased after administration of metformin. Metformin also upregulated the expression of mitochondrial biogenesis genes. Furthermore, the biochemical analysis demonstrated that metformin ameliorated the oxidative stress induced by cuprizone. Immunohistochemistry analysis showed that astrogliosis and microgliosis were decreased after metformin administration while it enhanced the number of oligodendrocytes. Our data implicated that metformin exerts its therapeutic effects on MS by AMPK signaling improved mitochondrial homeostasis and protected oligodendrocytes.


Assuntos
Metformina/administração & dosagem , Mitocôndrias/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Proteínas Quinases/genética , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Hemostasia/efeitos dos fármacos , Hemostasia/genética , Humanos , Camundongos , Mitocôndrias/genética , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
15.
Ann Clin Transl Neurol ; 6(2): 392-396, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30847372

RESUMO

Our objective was to examine the brain biopsies by histopathology and investigate the prognosis of patients with myelin oligodendrocyte glycoprotein antibody-associated demyelinating pseudotumor. The clinical, MRI, and histological features of two patients with myelin oligodendrocyte glycoprotein antibody-associated demyelinating pseudotumor were reviewed. Both patients were treated with steroid plus rituximab and followed up. The brain biopsies of both cases revealed T cells, macrophages, and complement-mediated demyelination, which was in accord with multiple sclerosis-like pathology. Moreover, both cases showed favorable response to steroid plus rituximab therapy. Our cases add a new variant to the myelin oligodendrocyte glycoprotein-encephalomyelitis spectrum, which favorably responds to immunotherapy.


Assuntos
Autoanticorpos/efeitos adversos , Doenças Desmielinizantes/induzido quimicamente , Glicoproteína Mielina-Oligodendrócito/metabolismo , Malformações do Sistema Nervoso/patologia , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/patologia , Encefalomielite/tratamento farmacológico , Encefalomielite/patologia , Humanos , Fatores Imunológicos/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Glicoproteína Associada a Mielina/metabolismo , Malformações do Sistema Nervoso/tratamento farmacológico , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo
16.
Glia ; 67(7): 1320-1332, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30815939

RESUMO

Oligodendrocytes (OLs) are the myelinating glia of the central nervous system. Injury to OLs causes myelin loss. In demyelinating diseases, such as multiple sclerosis, the remyelination is hindered principally due to a failure of the oligodendrocyte precursor cells (OPCs) to differentiate into mature OLs. To identify inducers of OPC to OL differentiation, a high-throughput screening based on myelin basic protein expression using neural progenitor cells-derived OPCs has been performed and, PD0325901-an MEK (MAPK kinase) inhibitor-is found to significantly enhance OPC to OL differentiation in a dose- and time-dependent manner. Other MEK inhibitors also display similar effect, indicating blockade of MAPK-ERK signaling is sufficient to induce OPC differentiation into OLs. PD0325901 facilitates the formation of myelin sheaths in OPC-neuron co-culture in vitro. And in experimental autoimmune encephalomyelitis model and cuprizone-induced demyelination model, PD0325901 displays significant therapeutic effect by promoting myelin regeneration. Our results suggest that targeting the MAPK-ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.


Assuntos
Doenças Desmielinizantes/enzimologia , Encefalomielite Autoimune Experimental/enzimologia , Sistema de Sinalização das MAP Quinases/fisiologia , Oligodendroglia/enzimologia , Recuperação de Função Fisiológica/fisiologia , Remielinização/fisiologia , Animais , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Técnicas de Cocultura , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Oligodendroglia/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Remielinização/efeitos dos fármacos
17.
Methods Mol Biol ; 1936: 227-238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820902

RESUMO

To study cellular and molecular mechanisms of demyelination and remyelination in vivo, we developed a transgenic zebrafish line, Tg(mbp:mCherry-NTR), in which expression of the bacterial enzyme nitroreductase (NTR) is driven under the myelin basic protein promoter (mbp) and thus is expressed in myelinating glia. When NTR-expressing larvae are treated with the prodrug metronidazole, the reaction between NTR and Mtz results in a toxic metabolite which selectively kills NTR-expressing cells. Using the Tg(mbp:mCherry-NTR) line, we can ablate two-thirds of oligodendrocytes following a 2-day MTZ treatment. Demyelination is evident seven days later, and remyelination is observed 16 days after Mtz treatment. The Tg(mbp:mCherry-NTR) model can be used to image cell behavior during, and to test how genetic manipulations or chemical compounds regulate, demyelination and remyelination. In this chapter, we describe the methods we used to characterize the oligodendrocyte loss, demyelination and remyelination in the Tg(mbp:mCherry-NTR) model.


Assuntos
Doenças Desmielinizantes/induzido quimicamente , Metronidazol/farmacologia , Nitrorredutases/metabolismo , Oligodendroglia/citologia , Peixe-Zebra/crescimento & desenvolvimento , Animais , Animais Geneticamente Modificados , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Proteína Básica da Mielina/genética , Neuroglia , Nitrorredutases/genética , Oligodendroglia/efeitos dos fármacos , Regiões Promotoras Genéticas , Remielinização/efeitos dos fármacos , Peixe-Zebra/genética
18.
Methods Mol Biol ; 1936: 377-396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820910

RESUMO

Clinical myelin diseases, and our best experimental approximations, are complex entities in which demyelination and remyelination proceed unpredictably and concurrently. These features can make it difficult to identify mechanistic details. Toxin-based models offer lesions with predictable spatiotemporal patterns and relatively discrete phases of damage and repair: a simpler system to study the relevant biology and how this can be manipulated. Here, we discuss the most widely used toxin-based models, with a focus on lysolecithin, ethidium bromide, and cuprizone. This includes an overview of their respective mechanisms, strengths, and limitations and step-by-step protocols for their use.


Assuntos
Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Remielinização , Animais , Cuprizona/toxicidade , Doenças Desmielinizantes/tratamento farmacológico , Modelos Animais de Doenças , Etídio/toxicidade , Lisofosfatidilcolinas/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Ratos
19.
J Neuroinflammation ; 16(1): 28, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736794

RESUMO

BACKGROUND: Inappropriate contact between the immune system and the central nervous system is thought to be a cause of demyelination. We previously reported the ability of the class IV semaphorin, Semaphorin4A (Sema4A), to induce apoptosis in human oligodendrocytes; however, these results have yet to be translated to an in vivo setting. Importantly, HIV-associated neurocognitive disorder remains a significant complication for patients on combined anti-retroviral therapy, with white matter damage seen on MRI. METHODS: Human cerebrospinal fluid and serum was assayed for Sema4A using a Sema4A-specific ELISA. Wild-type mice were injected with Sema4A via stereotaxic infusion. Data was assessed for significance using unpaired t tests, comparing the corpus callosum of PBS-injected mice versus Sema4A-injected mice. RESULTS: Here, we demonstrate elevated levels of Sema4A in the cerebrospinal fluid and serum of people with HIV infection. Furthermore, we demonstrate that direct injection of Sema4A into the corpus callosum of mice results in loss of myelin architecture and decreased myelin, concomitant with apoptosis of mature myelinating oligodendrocytes. Sema4A injection also causes increased activation of microglia. CONCLUSIONS: Taken together, our data further establish Sema4A as a potentially significant mediator of demyelinating diseases and a direct connection between the immune system and oligodendrocytes.


Assuntos
Doenças Desmielinizantes/induzido quimicamente , Oligodendroglia/efeitos dos fármacos , Semaforinas/farmacologia , Adulto , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Corpo Caloso , Doenças Desmielinizantes/patologia , Infecções por HIV/sangue , Infecções por HIV/líquido cefalorraquidiano , Humanos , Imuno-Histoquímica , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Semaforinas/administração & dosagem , Semaforinas/líquido cefalorraquidiano , Substância Branca/patologia
20.
J Physiol Biochem ; 75(1): 89-99, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30759305

RESUMO

Multiple sclerosis is among the most common causes of neurological disabilities in young adults. Over the past decade, several therapeutic strategies have emerged as having potential neuroprotective and neuroregenerative properties. We investigated the effect of intranasal administration of LINGO-1-directed siRNA-loaded chitosan nanoparticles on demyelination and remyelination processes in a rat model of demyelination. Adult male Wistar rats were randomly assigned to one of 6 groups (n = 10 each) and subjected to intrapontine stereotaxic injection of ethidium bromide (EB) to induce demyelination. EB-treated rats were either left untreated or received intranasal LINGO-1-directed siRNA-chitosan nanoparticles from day 1 to day 7 (demyelination group) or from day 7 to day 21 (remyelination group) after EB injection. Chitosan nanoparticle (50 µl) was given alone after EB stereotaxic injection for both demyelination and remyelination groups. Two additional groups received 10 µl of saline by stereotaxic injection, followed by intranasal saline as controls for demyelination and remyelination groups (n = 10/group). Behavioural testing was conducted for all rats, as well as terminal biochemical assays and pathological examination of pontine tissues were done. After EB injection, rats had compromised motor performance and coordination. Pathological evidence of demyelination was observed in pontine tissue and higher levels of caspase-3 activity were detected compared to control rats. With LINGO-1-directed siRNA-chitosan nanoparticle treatment, animals performed better than controls. Remyelination-treated group showed better motor performance than demyelination group. LINGO-1 downregulation was associated with signs of repair in histopathological sections, higher expression of pontine myelin basic protein (MBP) mRNA and protein and lower levels of caspase-3 activity indicating neuroprotection and remyelination enhancement.


Assuntos
Ataxia/terapia , Doenças Desmielinizantes/terapia , Proteínas de Membrana/antagonistas & inibidores , Nanopartículas/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/administração & dosagem , RNA Interferente Pequeno/genética , Remielinização/genética , Administração Intranasal , Animais , Ataxia/induzido quimicamente , Ataxia/genética , Ataxia/patologia , Caspase 3/genética , Caspase 3/metabolismo , Quitosana/química , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Portadores de Fármacos , Composição de Medicamentos/métodos , Etídio/toxicidade , Regulação da Expressão Gênica , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteína Básica da Mielina/agonistas , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Nanopartículas/administração & dosagem , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Núcleo Magno da Rafe/efeitos dos fármacos , Núcleo Magno da Rafe/metabolismo , Núcleo Magno da Rafe/patologia , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Técnicas Estereotáxicas
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