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1.
DNA Cell Biol ; 39(1): 3-7, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31851535

RESUMO

The chemokine receptor CXCR2 is a receptor for CXC chemokines, including CXCL1 and CXCL2. CXCR2 is expressed by resident cells of the central nervous system, including neurons, microglia, oligodendrocyte progenitor cells (OPCs), and oligodendrocytes. CXCR2 signaling is important in regulating OPC biology with regard to positional migration and myelination during development. More recently, studies have argued that CXCR2 is involved in controlling events related to remyelination after experimentally induced demyelination. This review examines the concept that targeting CXCR2 may offer a novel therapeutic target for promoting remyelination.


Assuntos
Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes/genética , Modelos Animais de Doenças , Receptores de Interleucina-8B/genética , Remielinização/genética , Transdução de Sinais/genética , Animais , Sistema Nervoso Central/citologia , Doenças Desmielinizantes/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Receptores de Interleucina-8B/metabolismo
2.
Adv Neurobiol ; 23: 347-361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667815

RESUMO

The astrocyte-neuron lactate transfer shuttle (ANLS) is one of the important metabolic systems that provides a physiological infrastructure for glia-neuronal interactions where specialized architectural organization supports the function. Perivascular astrocyte end-feet take up glucose via glucose transporter 1 to actively regulate glycogen stores, such that high ambient glucose upregulates glycogen and low levels of glucose deplete glycogen stores. A rapid breakdown of glycogen into lactate during increased neuronal activity or low glucose conditions becomes essential for maintaining axon function. However, it fails to benefit axon function during an ischemic episode in white matter (WM). Aging causes a remarkable change in astrocyte architecture characterized by thicker, larger processes oriented parallel to axons, as opposed to vertically-transposing processes. Subsequently, aging axons become more vulnerable to depleted glycogen, although aging axons can use lactate as efficiently as young axons. Lactate equally supports function during aglycemia in corpus callosum (CC), which consists of a mixture of myelinated and unmyelinated axons. Moreover, axon function in CC shows greater resilience to a lack of glucose compared to optic nerve, although both WM tracts show identical recovery after aglycemic injury. Interestingly, emerging evidence implies that a lactate transport system is not exclusive to astrocytes, as oligodendrocytes support the axons they myelinate, suggesting another metabolic coupling pathway in WM. Future studies are expected to unravel the details of oligodendrocyte-axon lactate metabolic coupling to establish that all WM components metabolically cooperate and that lactate may be the universal metabolite to sustain central nervous system function.


Assuntos
Envelhecimento/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Encéfalo/citologia , Encéfalo/metabolismo , Comunicação Celular , Glicogênio/metabolismo , Ácido Láctico/metabolismo , Axônios/metabolismo , Encéfalo/patologia , Glucose/metabolismo , Oligodendroglia/metabolismo
3.
BMC Genomics ; 20(1): 699, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31506062

RESUMO

BACKGROUND: Successful social behavior requires real-time integration of information about the environment, internal physiology, and past experience. The molecular substrates of this integration are poorly understood, but likely modulate neural plasticity and gene regulation. In the cichlid fish species Astatotilapia burtoni, male social status can shift rapidly depending on the environment, causing fast behavioral modifications and a cascade of changes in gene transcription, the brain, and the reproductive system. These changes can be permanent but are also reversible, implying the involvement of a robust but flexible mechanism that regulates plasticity based on internal and external conditions. One candidate mechanism is DNA methylation, which has been linked to social behavior in many species, including A. burtoni. But, the extent of its effects after A. burtoni social change were previously unknown. RESULTS: We performed the first genome-wide search for DNA methylation patterns associated with social status in the brains of male A. burtoni, identifying hundreds of Differentially Methylated genomic Regions (DMRs) in dominant versus non-dominant fish. Most DMRs were inside genes supporting neural development, synapse function, and other processes relevant to neural plasticity, and DMRs could affect gene expression in multiple ways. DMR genes were more likely to be transcription factors, have a duplicate elsewhere in the genome, have an anti-sense lncRNA, and have more splice variants than other genes. Dozens of genes had multiple DMRs that were often seemingly positioned to regulate specific splice variants. CONCLUSIONS: Our results revealed genome-wide effects of A. burtoni social status on DNA methylation in the brain and strongly suggest a role for methylation in modulating plasticity across multiple biological levels. They also suggest many novel hypotheses to address in mechanistic follow-up studies, and will be a rich resource for identifying the relationships between behavioral, neural, and transcriptional plasticity in the context of social status.


Assuntos
Encéfalo/metabolismo , Ciclídeos/genética , Metilação de DNA , Genômica , Animais , Comportamento Animal , Encéfalo/citologia , Neurônios GABAérgicos/metabolismo , Perfilação da Expressão Gênica , Hipotálamo/citologia , Hipotálamo/metabolismo , Oligodendroglia/metabolismo , Transdução de Sinais/genética , Meio Social
4.
Nat Commun ; 10(1): 4249, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534164

RESUMO

The first wave of oligodendrocyte precursor cells (firstOPCs) and most GABAergic interneurons share common embryonic origins. Cortical firstOPCs are thought to be replaced by other OPC populations shortly after birth, maintaining a consistent OPC density and making postnatal interactions between firstOPCs and ontogenetically-related interneurons unlikely. Challenging these ideas, we show that a cortical firstOPC subpopulation survives and forms functional cell clusters with lineage-related interneurons. Favored by a common embryonic origin, these clusters display unexpected preferential synaptic connectivity and are anatomically maintained after firstOPCs differentiate into myelinating oligodendrocytes. While the concomitant rescue of interneurons and firstOPCs committed to die causes an exacerbated neuronal inhibition, it abolishes interneuron-firstOPC high synaptic connectivity. Further, the number of other oligodendroglia populations increases through a non-cell-autonomous mechanism, impacting myelination. These findings demonstrate unprecedented roles of interneuron and firstOPC apoptosis in regulating lineage-related cell interactions and the homeostatic oligodendroglia density.


Assuntos
Apoptose/fisiologia , Interneurônios/metabolismo , Neurogênese/fisiologia , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/embriologia , Feminino , Neurônios GABAérgicos/citologia , Proteínas de Homeodomínio/metabolismo , Interneurônios/citologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/citologia
5.
Nat Commun ; 10(1): 4125, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511515

RESUMO

Vesicular release from neurons promotes myelin sheath growth on axons. Oligodendrocytes express proteins that allow dendrites to respond to vesicular release at synapses, suggesting that axon-myelin contacts use similar communication mechanisms as synapses to form myelin sheaths. To test this, we used fusion proteins to track synaptic vesicle localization and membrane fusion in zebrafish during developmental myelination and investigated expression and localization of PSD95, a dendritic post-synaptic protein, within oligodendrocytes. Synaptic vesicles accumulate and exocytose at ensheathment sites with variable patterning and most sheaths localize PSD95 with patterning similar to exocytosis site location. Disruption of candidate PDZ-binding transsynaptic adhesion proteins in oligodendrocytes cause variable effects on sheath length and number. One candidate, Cadm1b, localizes to myelin sheaths where both PDZ binding and extracellular adhesion to axons mediate sheath growth. Our work raises the possibility that axon-glial communication contributes to myelin plasticity, providing new targets for mechanistic unraveling of developmental myelination.


Assuntos
Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Sinapses/metabolismo , Animais , Axônios/metabolismo , Moléculas de Adesão Celular/metabolismo , Exocitose , Modelos Biológicos , Proteínas do Tecido Nervoso , Oligodendroglia/citologia , Vesículas Sinápticas/metabolismo , Fatores de Transcrição/metabolismo , Peixe-Zebra
6.
Iran J Allergy Asthma Immunol ; 18(3): 230-250, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522431

RESUMO

Toll-like receptors (TLRs) play principle roles in recognition of autologous components which have been pointed as the danger-associated molecular patterns (DAMP) and microbial components which are identified as pathogen associated molecular patterns (PAMP).The infiltration of various inflammatory cells such as dendritic cells, lymphocytes (CD4+ T, CD8+ T as well as B cells), monocytes and macrophages occur into the central nervous sys-tem (CNS) during multiple sclerosis (MS) and its animal model named experimental autoimmune encephalomyelitis (EAE). The infiltrated leukocytes and residential cells of the CNS express several TLRs (especially TLR2) and their expression are elevated in MS and EAE. TLR2 recognizes a large variety DAMP and PAMP molecules due to its ability to create heterodimers with TLR1, TLR6 and probably TLR10. A wide spectrum of  DAMP molecules, including heat shock protein 60 (HSP60), HSP70, high mobility group box 1 (HMGB1), ß-defensin 3, surfactant protein A and D, eosinophil-derived neurotoxin, gangliosides, serum amyloid A, hyaluronic acid and biglycan are identified by TLR2, whose their expression is increased in MS patients. TLR2 may contribute in the development of MS and EAE diseases through the reinforcement of Th1/Th17 cell-related responses, downregulation of regulatory T cells, induction of IL-17+ γδ T cells, inhibition of oligodendrocyte maturation, induction of poly ADP-ribose polymerase-1 (PARP-1)-dependent pathway in microglia, macrophages and astrocytes and inhibition of type I interferons expression. The contribution of TLR2-related immunopathological responses in the MS and EAE pathogenesis and its possible targeting as promising therapeutic potentials are considered in this review.


Assuntos
Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Comunicação Celular , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Ligantes , Macrófagos/imunologia , Macrófagos/metabolismo , Microglia/imunologia , Microglia/metabolismo , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Bainha de Mielina/imunologia , Bainha de Mielina/metabolismo , Oligodendroglia/citologia , Oligodendroglia/imunologia , Oligodendroglia/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética
7.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540019

RESUMO

Evidence has been accumulated demonstrating that heavy metals may accumulate in various organs, leading to tissue damage and toxic effects in mammals. In particular, the Central Nervous System (CNS) seems to be particularly vulnerable to cumulative concentrations of heavy metals, though the pathophysiological mechanisms is still to be clarified. In particular, the potential role of oligodendrocyte dysfunction and myelin production after exposure to subtoxic concentration I confirmed. It is ok of heavy metals is to be better assessed. Here we investigated on the effect of sub-toxic concentration of several essential (Cu2 +, Cr3 +, Ni2 +, Co2+) and non-essential (Pb2 +, Cd2+, Al3+) heavy metals on human oligodendrocyte MO3.13 and human neuronal SHSY5Y cell lines (grown individually or in co-culture). MO3.13 cells are an immortal human-human hybrid cell line with the phenotypic characteristics of primary oligodendrocytes but following the differentiation assume the morphological and biochemical features of mature oligodendrocytes. For this reason, we decided to use differentiated MO3.13 cell line. In particular, exposure of both cell lines to heavy metals produced a reduced cell viability of co-cultured cell lines compared to cells grown separately. This effect was more pronounced in neurons that were more sensitive to metals than oligodendrocytes when the cells were grown in co-culture. On the other hand, a significant reduction of lipid component in cells occurred after their exposure to heavy metals, an effect accompanied by substantial reduction of the main protein that makes up myelin (MBP) in co-cultured cells. Finally, the effect of heavy metals in oligodendrocytes were associated to imbalanced intracellular calcium ion concentration as measured through the fluorescent Rhod-2 probe, thus confirming that heavy metals, even used at subtoxic concentrations, lead to dysfunctional oligodendrocytes. In conclusion, our data show, for the first time, that sub-toxic concentrations of several heavy metals lead to dysfunctional oligodendrocytes, an effect highlighted when these cells are co-cultured with neurons. The pathophysiological mechanism(s) underlying this effect is to be better clarified. However, imbalanced intracellular calcium ion regulation, altered lipid formation and, finally, imbalanced myelin formation seem to play a major role in early stages of heavy metal-related oligodendrocyte dysfunction.


Assuntos
Metais Pesados/toxicidade , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular , Sistema Nervoso Central , Humanos , Metais Pesados/química , Bainha de Mielina/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/química , Neurônios/efeitos dos fármacos , Neurônios/patologia , Oligodendroglia/química , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia
8.
Nat Commun ; 10(1): 3455, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371763

RESUMO

The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion. Here, in a novel rat model, we recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutant rats, which were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with effects on mature oligodendrocytes, including aberrant intracellular distribution of myelin basic protein. Finally, we demonstrated effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.


Assuntos
Haploinsuficiência/fisiologia , Bainha de Mielina/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/metabolismo , Substância Branca/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Axônios/metabolismo , Axônios/patologia , Comportamento Animal , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Humanos , Masculino , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/patologia , Ratos
9.
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
10.
Int J Mol Sci ; 20(15)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387202

RESUMO

Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype. In the following manuscript, we review the evidence regarding glial dysfunction and its effects on disease etiology.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Proteína 2 de Ligação a Metil-CpG/deficiência , Neuroglia/metabolismo , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Animais , Astrócitos/metabolismo , Metabolismo Energético , Estudos de Associação Genética/métodos , Humanos , Oligodendroglia/metabolismo , Fenótipo , Síndrome de Rett/diagnóstico
11.
J Neuroinflammation ; 16(1): 161, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362762

RESUMO

BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). It is firmly established that overactivation of the p65 (RelA) nuclear factor kappa B (NF-κB) transcription factor upregulates expression of inflammatory mediators in both immune and non-immune resident CNS cells and promotes inflammation during MS. In contrast to p65, NF-κB family member RelB regulates immune cell development and can limit inflammation. Although RelB expression is induced during inflammation in the CNS, its role in MS remains unknown. METHODS: To examine the role of RelB in non-immune CNS cells, we generated mice with RelB specifically deleted in astrocytes (RelBΔAST), oligodendrocytes (RelBΔOLIGO), or neural progenitor-derived cells (RelBΔNP). We used experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS, to assess the effect of RelB deletion on disease outcomes and performed analysis on the histological, cellular, and molecular level. RESULTS: Despite being a negative regulator of inflammation, conditional knockout of RelB in non-immune resident CNS cells surprisingly decreased the severity of EAE. This protective effect was recapitulated by conditional deletion of RelB in oligodendrocytes but not astrocytes. Deletion of RelB in oligodendrocytes reduced disease severity, promoted survival of mature oligodendrocytes, and correlated with increased activation of p65 NF-κB. CONCLUSIONS: These findings suggest that RelB fine tunes inflammation and cell death/survival during EAE. Importantly, our data points out the detrimental role RelB plays in controlling survival of mature oligodendrocytes, which could be explored as a viable option to treat MS in the future.


Assuntos
Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Oligodendroglia/metabolismo , Fator de Transcrição RelB/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/patologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , NF-kappa B/metabolismo , Células-Tronco Neurais/metabolismo , Fator de Transcrição RelB/genética
12.
Nat Commun ; 10(1): 3887, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467299

RESUMO

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.


Assuntos
Antígenos/imunologia , Sistema Nervoso Central/imunologia , Doenças Desmielinizantes/imunologia , Células Precursoras de Oligodendrócitos/imunologia , Células Precursoras de Oligodendrócitos/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Astrócitos/metabolismo , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Caspase 3/metabolismo , Caspase 7/metabolismo , Diferenciação Celular , Sistema Nervoso Central/metabolismo , Citocinas/genética , Citocinas/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Expressão Gênica , Antígenos de Histocompatibilidade Classe I , Humanos , Interferon gama , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/metabolismo , Ovalbumina/metabolismo , Remielinização/imunologia , Linfócitos T
13.
BMC Neurosci ; 20(1): 33, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291887

RESUMO

BACKGROUND: Hypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3-6 months to induce chronic obesity. RESULTS: The transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein. CONCLUSIONS: Altogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Hipotálamo/metabolismo , Interleucina-33/metabolismo , Bainha de Mielina/patologia , Regulação para Cima , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Hipotálamo/patologia , Masculino , Camundongos , Proteína Básica da Mielina/biossíntese , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Cultura Primária de Células , Ratos , Fatores de Tempo
14.
Mol Biol Rep ; 46(5): 4817-4826, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31270757

RESUMO

Oligodendrocyte precursor cells (OPC) are a uniformly distributed population of glial cells that are well known for proliferating and differentiating into mature oligodendrocytes to form the myelin sheet in the central nervous system (CNS). Since monocarboxylate transporter 1 (MCT1) has shown to be expressed by oligodendroglia, the involvement of these cells with the metabolic support to axons has emerged as an important role in the maintenance of neuronal functionality. Hyperglycemia is a metabolic dysfunction highly associated with oxidative stress, a classical feature linked to many disorders such as diabetes mellitus. Despite of being widely investigated in several different cell cultures, including astrocytes and neurons, such condition has been poorly investigated in OPC culture. Thus, the aim of this study was to explore the possible effects of high-glucose exposure in acute and chronic conditions on oligodendroglial development and functionality in vitro. In this sense, we have demonstrated that under high-glucose exposure OPC improved its differentiation rate without affecting its membrane integrity and its morphology. Besides, chronic high-glucose condition also increased glucose uptake and lactate release. On the other hand, our findings also showed that, unlike what happens in other glial cells and neurons, high-glucose exposure did not seem to induce oxidative stress in OPC culture. Therefore, as far as we have investigated in this present study, we suggest that OPC may be able to support neurons and other glial cells during hyperglycemia events.


Assuntos
Diferenciação Celular , Metabolismo Energético , Glucose/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Animais , Biomarcadores , Glicemia , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glucose/farmacologia , Hiperglicemia/metabolismo , Imunofenotipagem , Ácido Láctico/biossíntese , Oligodendroglia/efeitos dos fármacos , Oxirredução , Ratos
15.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340538

RESUMO

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Córtex Cerebral/metabolismo , Nanismo/genética , Epilepsia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/genética , Neurogênese/genética , Transtornos Psicomotores/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Antiporters/genética , Antiporters/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Contagem de Células , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Modelos Animais de Doenças , Nanismo/metabolismo , Nanismo/patologia , Epilepsia/metabolismo , Epilepsia/patologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação em Linhagem Germinativa , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Masculino , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/patologia , Ratos , Ratos Transgênicos , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência , Oxidorredutase com Domínios WW/deficiência
16.
J Neuroinflammation ; 16(1): 158, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31351476

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by both inflammatory demyelination and impaired remyelination. Studies indicate that Toll-like receptor 2 (TLR2) signaling contributes to both the inflammatory component and the defective remyelination in MS. While most MS therapeutics target adaptive immunity, we recently reported that reducing TLR2 signaling in innate immune cells by inducing TLR2 tolerance attenuates adoptively transferred experimental autoimmune encephalomyelitis. Given that previous reports suggest TLR2 signaling also inhibits myelin repair, the objective of this study was to assess how reducing TLR2 signaling through TLR2 tolerance induction affects CNS myelin repair. METHODS: Chow containing 0.2% cuprizone was fed to male and female wild-type (WT) C57BL/6 mice or TLR2-deficient (TLR2-/-) mice for 5 weeks to induce demyelination. During a 2-week remyelination period following discontinuation of cuprizone, WT mice received either low dose TLR2 ligands to induce systemic TLR2 tolerance or vehicle control (VC). Remyelination was evaluated via electron microscopy and immunohistochemical analysis of microglia and oligodendrocytes in the corpus callosum. Statistical tests included 2-way ANOVA and Mann-Whitney U analyses. RESULTS: Inducing TLR2 tolerance in WT mice during remyelination significantly enhanced myelin recovery, restoring unmyelinated axon frequency and myelin thickness to baseline levels compared to VC-treated mice. Mechanistically, enhanced remyelination in TLR2 tolerized mice was associated with a shift in corpus callosum microglia from a pro-inflammatory iNOS+ phenotype to a non-inflammatory/pro-repair Arg1+ phenotype. This result was confirmed in vitro by inducing TLR2 tolerance in WT microglia cultures. TLR2-/- mice, without TLR2 tolerance induction, also significantly enhanced myelin recovery compared to WT mice, adding confirmation that reduced TLR2 signaling is associated with enhanced remyelination. DISCUSSION: Our results suggest that reducing TLR2 signaling in vivo by inducing TLR2 tolerance significantly enhances myelin repair. Furthermore, the enhanced remyelination resulting from TLR2 tolerance induction is associated with a shift in corpus callosum microglia from a pro-inflammatory iNOS+ phenotype to a non-inflammatory/pro-repair Arg1+ phenotype. While deletion of TLR2 would be an impractical approach in vivo, reducing innate immune signaling through TLR2 tolerance induction may represent a novel, two-pronged approach for treating both inflammatory and myelin repair components of MS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Lipopeptídeos/uso terapêutico , Microglia/metabolismo , Oligodendroglia/metabolismo , Remielinização/fisiologia , Receptor 2 Toll-Like/metabolismo , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Resultado do Tratamento
17.
J Steroid Biochem Mol Biol ; 194: 105432, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31344443

RESUMO

Oxidative stress and mitochondrial dysfunction contribute to the pathogenesis of neurodegenerative diseases and favor lipid peroxidation, leading to increased levels of 7ß-hydroxycholesterol (7ß-OHC) which induces oxiapoptophagy (OXIdative stress, APOPTOsis, autoPHAGY). The cytoprotective effects of dimethylfumarate (DMF), used in the treatment of relapsing remitting multiple sclerosis and of monomethylfumarate (MMF), its main metabolite, were evaluated on murine oligodendrocytes 158 N exposed to 7ß-OHC (50 µM, 24 h) with or without DMF or MMF (25 µM). The activity of 7ß-OHC in the presence or absence DMF or MMF was evaluated on several parameters: cell adhesion; plasma membrane integrity measured with propidium iodide (PI), trypan blue and fluoresceine diacetate (FDA) assays; LDH activity; antioxidant enzyme activities (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)); generation of lipid peroxidation products (malondialdehyde (MDA), conjugated dienes (CDs)) and protein oxidation products (carbonylated proteins (CPs)); reactive oxygen species (ROS) overproduction conducted with DHE and DHR123. The effect on mitochondria was determined with complementary criteria: measurement of succinate dehydrogenase activity, evaluation of mitochondrial potential (ΔΨm) and mitochondrial superoxide anions (O2●-) production using DiOC6(3) and MitoSOX, respectively; quantification of mitochondrial mass with Mitotracker Red, and of cardiolipins and organic acids. The effects on mitochondrial and peroxisomal ultrastructure were determined by transmission electron microscopy. Intracellular sterol and fatty acid profiles were determined. Apoptosis and autophagy were characterized by staining with Hoechst 33,342, Giemsa and acridine orange, and with antibodies raised against caspase-3 and LC3. DMF and MMF attenuate 7ß-OHC-induced cytotoxicity: cell growth inhibition; decreased cell viability; mitochondrial dysfunction (decrease of succinate dehydrogenase activity, loss of ΔΨm, increase of mitochondrial O2●- production, alteration of the tricarboxilic acid (TCA) cycle, and cardiolipins content); oxidative stress induction (ROS overproduction, alteration of GPx, CAT, and SOD activities, increased levels of MDA, CDs, and CPs); changes in fatty acid and cholesterol metabolism; and cell death induction (caspase-3 cleavage, activation of LC3-I in LC3-II). Ultrastructural alterations of mitochondria and peroxisomes were prevented. These results demonstrate that DMF and MMF prevent major dysfunctions associated with neurodegenerative diseases: oxidative stress, mitochondrial dysfunction, apoptosis and autophagy.


Assuntos
Fumarato de Dimetilo/farmacologia , Fumaratos/farmacologia , Maleatos/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , Hidroxicolesteróis/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Estresse Oxidativo/efeitos dos fármacos
18.
Biomed Environ Sci ; 32(4): 291-299, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31217065

RESUMO

OBJECTIVE: Age-related diseases, including neurodegenerative diseases, are associated with oxidative stress and lipid peroxidation, and increase the levels of cholesterol auto-oxidation products such as 7ß-hydroxycholesterol (7ß-OHC). Thus, it is imperative to identify agents that can prevent 7ß-OHC-induced side-effects. METHODS: We evaluated the potential protective effects of Carpobrotus edulis ethanol-water extract (EWe) on murine oligodendrocytes (158N) cultured in the absence or presence of 7ß-OHC (20 µg/mL, 24 h). The cells were incubated with EWe (20-200 µg/mL) 2 h before 7ß-OHC treatment. Mitochondrial activity and cell growth were evaluated with the MTT assay. Photometric methods were used to analyze antioxidant enzyme [catalase (CAT) and glutathione peroxidase (GPx)] activities and the generation of lipid and protein oxidation products [malondialdehyde (MDA), conjugated diene (CD), and carbonylated proteins (CPs)]. RESULTS: Treatment with 7ß-OHC induced cell death and oxidative stress (reflected by alteration in CAT and SOD activities). Overproduction of lipid peroxidation products (MDA and CDs) and CPs was also reported. The cytotoxic effects associated with 7ß-OHC were attenuated by 160 µg/mL of EWe of C. edulis. Cell death induced by 7ß-OHC treatment was ameliorated, GPx and CAT activities were restored to normal, and MDA, CD, and CP levels were reduced following C. edulis extract treatment. CONCLUSION: These data demonstrate the protective activities of C. edulis EWe against 7ß-OHC-induced disequilibrium in the redox status of 158N cells, indicative of the potential role of this plant extract in the prevention of neurodegenerative diseases.


Assuntos
Aizoaceae , Doenças Neurodegenerativas/prevenção & controle , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Hidroxicolesteróis , Camundongos , Neuroproteção , Oligodendroglia/metabolismo , Fitoterapia , Extratos Vegetais/uso terapêutico
19.
PLoS Biol ; 17(6): e3000330, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31226122

RESUMO

The repair of white matter damage is of paramount importance for functional recovery after brain injuries. Here, we report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 d after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific peroxisome proliferator-activated receptor gamma (PPARγ) knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the central nervous system (CNS), which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.


Assuntos
Interleucina-4/metabolismo , Oligodendroglia/metabolismo , PPAR gama/metabolismo , Animais , Lesões Encefálicas , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Diferenciação Celular/fisiologia , Doenças Desmielinizantes/metabolismo , Interleucina-4/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Bainha de Mielina/metabolismo , Regeneração Nervosa , Neurogênese , Oligodendroglia/fisiologia , PPAR gama/fisiologia , Recuperação de Função Fisiológica , Remielinização/fisiologia , Transdução de Sinais , Acidente Vascular Cerebral , Substância Branca
20.
Neurochem Res ; 44(8): 1893-1902, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31209727

RESUMO

The trigeminal root entry zone (TREZ) is the transitional zone of central and peripheral tissue compartments in the trigeminal root. Microvascular compression on the TREZ is the main etiology of most idiopathic trigeminal neuralgia (TN) patients. However, the pathogenesis of TN is still uncertain. To investigate the glial plasticity changes in oligodendrocytes, Schwann cells, astrocytes and microglia/macrophages in the TREZ in TN, immunohistochemical staining and Western blot methods were performed in rats with TN induced by compression injury. The results showed that mechanical compression injury in the trigeminal nerve of the TN rats induced glial plasticity in the TREZ, which dynamically changed the glial interface of the CNS-PNS transitional zone. Additionally, glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte processes significantly proliferated and extended distally from the central region to the peripheral side of the TREZ after nerve compression injury in the TN group. Moreover, the expression of p75 in Schwann cells was upregulated on the peripheral side of the TREZ, and activated Iba-1-immunoreactive microglia/macrophages were observed on both sides of the TREZ. A significantly higher number of Schwann cells, astrocytes and microglia/macrophages were found in the TN group than in the sham operation group (p < 0.05). In conclusion, mechanical compression injury in the TN rats activated various glial cells, including oligodendrocytes, astrocytes, Schwann cells and microglia/macrophages, in the CNS-PNS transitional zone of TREZ. Changes in glial cell plasticity in the TREZ after compression injury might be involved in TN pathogenesis.


Assuntos
Neuroglia/metabolismo , Plasticidade Neuronal/fisiologia , Nervo Trigêmeo/metabolismo , Neuralgia do Trigêmeo/fisiopatologia , Animais , Astrócitos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Microglia/metabolismo , Oligodendroglia/metabolismo , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Nervo Trigêmeo/fisiopatologia , Traumatismos do Nervo Trigêmeo/fisiopatologia
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