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1.
Neurobiol Aging ; 106: 343.e1-343.e8, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34274155

RESUMO

We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.


Assuntos
Éxons/genética , Demência Frontotemporal/genética , Estudos de Associação Genética/métodos , Heterozigoto , Íntrons/genética , Transtornos Parkinsonianos/genética , Mutação Puntual/genética , Proteínas tau/genética , Idoso , Encéfalo/diagnóstico por imagem , Cromossomos Humanos Par 17/genética , Feminino , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/genética , Neuroimagem , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Tauopatias/genética
2.
PLoS One ; 15(4): e0226050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240164

RESUMO

Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80+ CD11b+ cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.


Assuntos
Encefalomielite Autoimune Experimental/genética , Lisofosfolipídeos/genética , Esclerose Múltipla/genética , Diester Fosfórico Hidrolases/genética , Animais , Antígeno CD11b/genética , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/fisiopatologia , Deleção de Genes , Expressão Gênica/genética , Humanos , Lisofosfolipídeos/biossíntese , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Esclerose Múltipla/sangue , Esclerose Múltipla/fisiopatologia , Transdução de Sinais/genética , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
3.
Acta Neuropathol Commun ; 8(1): 13, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019610

RESUMO

Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer's disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species ("seeds") containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.


Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Anticorpos Monoclonais/imunologia , Imunização Passiva/métodos , Proteínas tau/genética , Proteínas tau/imunologia , Doença de Alzheimer/patologia , Animais , Anticorpos Monoclonais/farmacologia , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Masculino , Camundongos Transgênicos , Agregação Patológica de Proteínas/imunologia , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/farmacologia
4.
Mol Genet Genomic Med ; 8(3): e1090, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31943857

RESUMO

BACKGROUND: Mutations in the GBA gene that encodes the lysosomal enzyme acid ß-glucocerebrosidase cause Gaucher disease (GD), the most common lysosomal storage disorder. Most of the mutations are missense/nonsense, however, a few splicing mutations within or close to conserved consensus donor or acceptor splice sites have also been described. The aim of the study was to identify the mutation(s) in a Cypriot patient with type I GD. METHODS: The genomic DNA of the proband was screened for nine common mutations using Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. All exons and exon-intron boundaries, and the 5'UTR and 3'UTR regions of the GBA gene, were investigated by Sanger sequencing. RNA analysis was performed using standard procedures, and the abnormal transcript was further cloned into pGEM-T-Easy plasmid vector and sequenced. The relevant intronic region was further sequenced by the Sanger method to identify the genetic variant. RESULTS: A novel point mutation, g.12599C > A (c.999 + 242C > A), was detected deep in intron 7 of the GBA gene. This type of mutation has been previously described for other diseases but this is the first time, as far as we know, that it is described for GD. This mutation creates a new donor splice site leading to aberrant splicing and resulting in the insertion of the first 239nt of intron 7 as a pseudoexon in the mRNA, creating a premature stop codon. CONCLUSION: This study expands the mutation spectrum of GD and highlights the importance of RNA sequencing for the molecular diagnosis of patients bearing mutations in nonexonic regions.


Assuntos
Doença de Gaucher/genética , Glucosilceramidase/genética , Mutação Puntual , Adulto , Feminino , Doença de Gaucher/patologia , Testes Genéticos/métodos , Humanos , Íntrons , Sítios de Splice de RNA , RNA-Seq/métodos
5.
Front Cell Neurosci ; 12: 404, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524237

RESUMO

Aberrant or chronic microglial activation is strongly implicated in neurodegeneration, where prolonged induction of classical inflammatory pathways may lead to a compromised blood-brain barrier (BBB) or vasculature, features of many neurodegenerative disorders and implicated in the observed cognitive decline. BBB disruption or vascular disease may expose the brain parenchyma to "foreign" plasma proteins which subsequently impact on neuronal network integrity through neurotoxicity, synaptic loss and the potentiation of microglial inflammation. Here we show that the blood coagulation factor fibrinogen (FG), implicated in the pathogenesis of dementias such as Alzheimer's disease (AD), induces an inflammatory microglial phenotype as identified through genetic microarray analysis of a microglial cell line, and proteome cytokine profiling of primary microglia. We also identify a FG-mediated induction of non-cell autonomous ER stress-associated neurotoxicity via a signaling pathway that can be blocked by pharmacological inhibition of microglial TNFα transcription or neuronal caspase-12 activity, supporting a disease relevant role for plasma components in neuronal dysfunction.

6.
Br J Pharmacol ; 174(16): 2662-2681, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28677901

RESUMO

BACKGROUND AND PURPOSE: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity. EXPERIMENTAL APPROACH: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans. KEY RESULTS: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity. CONCLUSIONS AND IMPLICATIONS: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity.


Assuntos
Benzamidas/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Canais de Potássio Ativados por Cálcio de Condutância Alta/fisiologia , Espasticidade Muscular/tratamento farmacológico , Animais , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Cães , Método Duplo-Cego , Endocanabinoides/química , Endocanabinoides/farmacocinética , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Feminino , Hepatócitos/metabolismo , Isomerismo , Macaca , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Knockout , Coelhos , Ratos Sprague-Dawley , Ratos Wistar , Receptor CB1 de Canabinoide/genética , Receptores de Canabinoides/genética , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologia
7.
PLoS One ; 11(6): e0157754, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27355629

RESUMO

Multiple sclerosis (MS) is a debilitating immune-mediated neurological disorder affecting young adults. MS is primarily relapsing-remitting, but neurodegeneration and disability accumulate from disease onset. The most commonly used mouse MS models exhibit a monophasic immune response with fast accumulation of neurological damage that does not allow the study of progressive neurodegeneration. The chronic relapsing and secondary progressive EAE (pEAE) Biozzi ABH mouse model of MS exhibits a reproducible relapsing-remitting disease course that slowly accumulates permanent neurological deficit and develops a post-relapsing progressive disease that permits the study of demyelination and neurodegeneration. RNA sequencing (RNAseq) was used to explore global gene expression in the pEAE Biozzi ABH mouse. Spinal cord tissue RNA from pEAE Biozzi ABH mice and healthy age-matched controls was sequenced. 2,072 genes were differentially expressed (q<0.05) from which 1,397 were significantly upregulated and 675 were significantly downregulated. This hypothesis-free investigation characterised the genomic changes that describe the pEAE mouse model. The differentially expressed genes revealed a persistent immunoreactant phenotype, combined with downregulation of the cholesterol biosynthesis superpathway and the LXR/RXR activation pathway. Genes differentially expressed include the myelination genes Slc17a7, Ugt8A and Opalin, the neuroprotective genes Sprr1A, Osm and Wisp2, as well as genes identified as MS risk factors, including RGs14 and Scap2. Novel genes with unestablished roles in EAE or MS were also identified. The identification of differentially expressed novel genes and genes involved in MS pathology, opens the door to their functional study in the pEAE mouse model which recapitulates some of the important clinical features of progressive MS.


Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Análise de Sequência de RNA , Medula Espinal/metabolismo , Transcrição Gênica , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Masculino , Camundongos , Camundongos Biozzi , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Fenótipo , Fatores de Risco
8.
PLoS One ; 8(7): e70941, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23923032

RESUMO

Rheumatoid arthritis (RA) is a destructive arthropathy with systemic manifestations, characterized by chronic synovial inflammation. Under the influence of the pro-inflammatory milieu synovial fibroblasts (SFs), the main effector cells in disease pathogenesis become activated and hyperplastic while releasing a number of signals that include pro-inflammatory factors and tissue remodeling enzymes. Activated RA SFs in mouse or human arthritic joints express significant quantities of autotaxin (ATX), a lysophospholipase D responsible for the majority of lysophosphatidic acid (LPA) production in the serum and inflamed sites. Conditional genetic ablation of ATX from SFs resulted in attenuation of disease symptoms in animal models, an effect attributed to diminished LPA signaling in the synovium, shown to activate SF effector functions. Here we show that administration of 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA), a metabolically stabilized analog of LPA and a dual function inhibitor of ATX and pan-antagonist of LPA receptors, attenuates collagen induced arthritis (CIA) development, thus validating the ATX/LPA axis as a novel therapeutic target in RA.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Lisofosfolipídeos/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Colágeno/efeitos adversos , Ativação Enzimática/efeitos dos fármacos , Feminino , Hidrólise/efeitos dos fármacos , Lisofosfatidilcolinas/metabolismo , Lisofosfolipídeos/farmacologia , Camundongos , Diester Fosfórico Hidrolases/metabolismo , Especificidade por Substrato
9.
Biochim Biophys Acta ; 1831(1): 42-60, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22867755

RESUMO

Lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), the most prominent lysoglycerophospholipids, are emerging as a novel class of inflammatory lipids, joining thromboxanes, leukotrienes and prostaglandins with which they share metabolic pathways and regulatory mechanisms. Enzymes that participate in LPC and LPA metabolism, such as the phospholipase A(2) superfamily (PLA(2)) and autotaxin (ATX, ENPP2), play central roles in regulating LPC and LPA levels and consequently their actions. LPC/LPA biosynthetic pathways will be briefly presented and LPC/LPA signaling properties and their possible functions in the regulation of the immune system and chronic inflammation will be reviewed. Furthermore, implications of exacerbated LPC and/or LPA signaling in the context of chronic inflammatory diseases, namely rheumatoid arthritis, multiple sclerosis, pulmonary fibrosis and hepatitis, will be discussed. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.


Assuntos
Inflamação/enzimologia , Lisofosfatidilcolinas/metabolismo , Lisofosfolipídeos/metabolismo , Fosfolipases A2/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Animais , Doença Crônica , Humanos , Inflamação/patologia , Transdução de Sinais
10.
J Exp Med ; 209(5): 925-33, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22493518

RESUMO

Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX expression from SFs was induced by TNF, and LPA induced SF activation and effector functions in synergy with TNF. Conditional genetic ablation of ATX in mesenchymal cells, including SFs, resulted in disease attenuation in animal models of arthritis, establishing the ATX/LPA axis as a novel player in chronic inflammation and the pathogenesis of arthritis and a promising therapeutic target.


Assuntos
Artrite Experimental/fisiopatologia , Artrite Reumatoide/fisiopatologia , Fibroblastos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , RNA Mensageiro/metabolismo , Membrana Sinovial/citologia , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Cromatografia Líquida , Galactosídeos , Deleção de Genes , Humanos , Imuno-Histoquímica , Indóis , Lisofosfolipídeos/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Knockout , Diester Fosfórico Hidrolases/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/metabolismo
11.
J Neurochem ; 112(2): 552-63, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19895660

RESUMO

Microglial activation can lead to microglial apoptosis, which may serve to remove highly reactive and possibly neurotoxic microglia. However the loss of microglia may have consequences for future recovery, protection and repair. P53, a nuclear phosphoprotein transcription factor, is critical for activating the expression of genes involved in cell-cycle arrest and stress-induced apoptosis. In neurodegenerative diseases the expression of p53 is significantly increased in glial cells, and microglial numbers fall. Following activation with chromogranin A (100 nM), or beta-amyloid(25-35), (10 microM), microglia became apoptotic. Furthermore, p53 expression was enhanced, peaking at 4-6 h after exposure to activators. The p53 transcription inhibitor, pifithrin-alpha, (10 microM) significantly reduced the expression of p53 in microglia and significantly modulated the levels of microglial apoptosis induced by activation. Lithium chloride (5 mM), which can modulate p53-mediated pathways, also reduced p53 expression and reduced microglial apoptosis suggesting glycogen synthase kinase-3 plays a role. Regulating p53 pathways modulated microglial inducible nitric oxide synthase expression and tumour necrosis factor alpha secretion. Inhibiting p53 mediated microglial apoptosis prevented microglial neurotoxicity suggesting targeting of p53-mediated pathways in microglia may have therapeutic benefit in Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fragmentos de Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Adjuvantes Imunológicos/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Células Cultivadas , Cerebelo/citologia , Cromogranina A/farmacologia , Interações Medicamentosas , Ensaio de Imunoadsorção Enzimática/métodos , Cloreto de Lítio/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Polissacarídeos/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo , Tolueno/análogos & derivados , Tolueno/farmacologia , Fator de Transcrição CHOP/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores
12.
FEBS Lett ; 583(21): 3461-6, 2009 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-19800883

RESUMO

Chromogranin A (CgA), a neuroactive glycoprotein, is associated with microglial activation cascades implicated in neurodegeneration. Here we show that CgA-dependent inducible nitric oxide synthase (iNOS) expression and stress responses in microglia involved signalling via scavenger receptors (SR), since SR class-A (SR-A) ligands blocked iNOS expression, mitochondrial depolarisation, apoptosis and glutamate release. Furthermore, block of SR-A ameliorated CgA-induced microglial neurotoxicity. In contrast, block of CD36, or the receptor for advanced glycation end products (RAGE) did not prevent CgA-induced microglial activation and neurotoxicity. Thus, manipulation of specific scavenger receptor-coupled signalling pathways may provide avenues for therapeutic intervention in neurodegenerative diseases implicating microglial activation with chromogranin peptides.


Assuntos
Cromogranina A/toxicidade , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurotoxinas/toxicidade , Receptores Depuradores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular , Cromogranina A/química , Dados de Sequência Molecular , Neurotoxinas/química , Placa Amiloide/efeitos dos fármacos , Placa Amiloide/metabolismo , Ratos , Ratos Wistar , Receptores Depuradores Classe A/metabolismo
13.
J Neurochem ; 109(3): 694-705, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19187440

RESUMO

Microglial activation by blood-borne factors following blood-brain barrier damage may play a significant role in subsequent neuropathogenesis of several neurodegenerative diseases. Exposure of primary cultured rat brain microglia to pure, fatty acid- and lipid-deficient rat serum albumin or fraction V, (fatty acid and lipid-containing rat serum albumin), caused inducible nitric oxide synthase (iNOS) expression, glutamate release, tumour necrosis factor alpha (TNFalpha) and transforming growth factor-beta1 release. iNOS expression was attenuated by the MAPK/extracellular signal-regulated kinase pathway inhibitor U0126 and the phosphorylated forms of extracellular signal-regulated kinase 1 and 2 were detectable in microglia treated with albumin or fraction V. Glutamate release was prevented by l-alpha-aminoadipate and glutathione levels in microglia rose on exposure to albumin. Conditioned medium from microglia exposed to albumin or fraction V was neurotoxic. Peripheral macrophages were resistant to the effects of albumin but both microglia and macrophages responded to lipopolysaccharide, which induced interleukin-1 beta and tumour necrosis factor alpha release, cyclooxygenase-2 and iNOS expression in both cell types, indicating a discrete desensitised pathway in macrophages for albumin which was not desensitised in microglia. Thus, exposure of microglia in the brain to albumin may contribute to neuronal damage following blood-brain barrier breakdown and point to resident microglia rather than infiltrating macrophages as therapeutic targets.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Microglia/efeitos dos fármacos , Albumina Sérica/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Animais Recém-Nascidos , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Meios de Cultivo Condicionados/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/química , Microglia/química , Neurônios/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Polimixina B/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo
14.
J Neurochem ; 106(1): 442-54, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18419765

RESUMO

Microglia are present in an activated state in multiple sclerosis lesions. Incubation of primary cultured rat microglia with rat-brain derived myelin (0.1-1 microg/mL) for 24 h induced microglial activation; cells displayed enhanced ED1 staining, expression of inducible nitric oxide synthase, production and release of the cytokine tumour necrosis factor-alpha and glutamate release. Exposure of microglia to myelin induced the expression of neuronal caspases and ultimately neuronal death in cultured cerebellar granule cell neurons; neurotoxicity was directly because of microglial-derived soluble toxins. Co-incubation of microglia with agonists or antagonists of different metabotropic glutamate receptor (mGluR) subtypes ameliorated microglial neurotoxicity by inhibiting soluble neurotoxin production. Activation of microglial mGluR2 exacerbated myelin-evoked neurotoxicity whilst activation of mGluR3 was protective as was activation of group III mGluRs. These data show that myelin-induced microglial neurotoxicity can be prevented by regulation of mGluRs and suggest these receptors on microglia may be promising targets for therapeutic intervention in multiple sclerosis.


Assuntos
Gliose/induzido quimicamente , Microglia/efeitos dos fármacos , Proteínas da Mielina/toxicidade , Degeneração Neural/induzido quimicamente , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Animais , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células Cultivadas , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Gliose/metabolismo , Gliose/fisiopatologia , Ácido Glutâmico/metabolismo , Microglia/metabolismo , Bainha de Mielina/química , Bainha de Mielina/metabolismo , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Neurotoxinas/metabolismo , Neurotoxinas/toxicidade , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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