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[PMID]:28457906
[Au] Autor:Üçal M; Haindl MT; Adzemovic MZ; Strasser J; Theisl L; Zeitelhofer M; Kraitsy K; Ropele S; Schäfer U; Fazekas F; Hochmeister S
[Ad] Endereço:Research Unit of Experimental Neurotraumatology, Department of Neurosurgery, Medical University Graz, Auenbruggerplatz 2.2, 8036 Graz, Austria.
[Ti] Título:Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG-immunized rats.
[So] Source:Exp Neurol;294:32-44, 2017 08.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cortical demyelination is a common finding in patients with chronic multiple sclerosis (MS) and contributes to disease progression and overall disability. The exact pathomechanism that leads to cortical lesions is not clear. Research is limited by the fact that standard animal models of multiple sclerosis do not commonly affect the cortex, or if they do in some variants, the cortical demyelination is rather sparse and already remyelinated within a few days. In an attempt to overcome these limitations we implanted a tissue-compatible catheter into the cortex of Dark Agouti rats. After 14days the rats were immunized with 5µg myelin oligodendrocyte glycoprotein (MOG) in incomplete Freund's Adjuvant, which did not cause any clinical signs but animals developed a stable anti-MOG antibody titer. Then the animals received an injection of proinflammatory cytokines through the catheter. This led to a demyelination of cortical and subcortical areas starting from day 1 in a cone-like pattern spreading from the catheter area towards the subarachnoid space. On day 3 cortical demyelination already expanded to the contralateral hemisphere and reached its peak between days 9-15 after cytokine injection with a widespread demyelination of cortical and subcortical areas of both hemispheres. Clinically the animals showed only discrete signs of fatigue and recovered completely after day 15. Even on day 30 we still were able to detect demyelination in subpial and intracortical areas along with areas of partial and complete remyelination. Loss of cortical myelin was accompanied with marked microglia activation. A second injection of cytokines through the catheter on day 30 led to a second demyelination phase with the same symptoms, but again no detectable motor dysfunction. Suffering of the animals appeared minor compared to standard Experimental Autoimmune Encephalomyelitis and therefore, even long-term observation and repeated demyelination phases seem ethically acceptable.
[Mh] Termos MeSH primário: Córtex Cerebral/patologia
Citocinas/toxicidade
Doenças Desmielinizantes/induzido quimicamente
Doenças Desmielinizantes/patologia
Encefalomielite Autoimune Experimental/patologia
Lateralidade Funcional/fisiologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Ligação ao Cálcio/metabolismo
Caspase 3/metabolismo
Citocinas/metabolismo
Modelos Animais de Doenças
Encefalomielite Autoimune Experimental/induzido quimicamente
Encefalomielite Autoimune Experimental/diagnóstico por imagem
Encefalomielite Autoimune Experimental/imunologia
Fibrina/metabolismo
Adjuvante de Freund/efeitos adversos
Lateralidade Funcional/efeitos dos fármacos
Imunização/efeitos adversos
Lipídeos/efeitos adversos
Masculino
Proteínas dos Microfilamentos/metabolismo
Microscopia Confocal
Atividade Motora
Proteína Proteolipídica de Mielina/metabolismo
Glicoproteína Associada a Mielina/efeitos adversos
Glicoproteína Associada a Mielina/sangue
Proteínas do Tecido Nervoso/metabolismo
Ratos
Estatísticas não Paramétricas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aif1 protein, rat); 0 (Calcium-Binding Proteins); 0 (Cytokines); 0 (Lipids); 0 (Microfilament Proteins); 0 (Myelin Proteolipid Protein); 0 (Myelin-Associated Glycoprotein); 0 (Nerve Tissue Proteins); 0 (incomplete Freund's adjuvant); 9001-31-4 (Fibrin); 9007-81-2 (Freund's Adjuvant); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180218
[Lr] Data última revisão:
180218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


  2 / 9823 MEDLINE  
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[PMID]:27771353
[Au] Autor:Peng W
[Ad] Endereço:Institute of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan 637000, P. R. China; Laboratory of Experimental Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus, Sderot Churchill, Jerusalem, 91240, Israel. Electronic address: pengwei39@hotmail.com.
[Ti] Título:G-CSF treatment promotes apoptosis of autoreactive T cells to restrict the inflammatory cascade and accelerate recovery in experimental allergic encephalomyelitis.
[So] Source:Exp Neurol;289:73-84, 2017 03.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:G-CSF is a hematopoietic growth factor that regulates the proliferation, differentiation and survival of myeloid lineage cells, which has protective effects in autoimmune neuroinflammatory diseases such as EAE. Here we use EAE model treated by G-CSF to address the hypothesis that G-CSF inhibits the proliferative response of splenic T cells via the enhancement of apoptosis, and this priming effect of G-CSF depends on the cell cycle. Our results show that G-CSF administration reduced EAE frequency and severity of attacks. The inflammatory cells and demyelination areas were decreased in the CNS of G-CSF-treated mice. G-CSF treatment altered cytokine profiles in vivo to inhibit the productions of IFN-γ, IL-1ß, IL-2, TNF-α, IL-17 and NO, while the secretions of IL-4 and IL-10 were increased. Splenic T cells from G-CSF-treated mice showed significantly lower proliferative response to specific antigen MOG stimulation. G-CSF enhanced the percentage of a CD4 CD25 T cell subset in spleen T cells. Moreover, G-CSF promoted the G0/G1 to S phase transition of MOG autoreactive T cells inducing apoptosis and elevating Bax gene expression of apoptosis marker. These findings indicate that G-CSF treatment induces the apoptosis of MOG autoreactive T cells, which decreases the production of pro-inflammatory cytokines and NO, suppresses the proliferation of autoreactive T cells and elevates a CD4 CD25 T cell subset to inhibit inflammatory infiltration and demyelination within CNS of EAE. The conclusions of G-CSF treatment in EAE mice suggest that G-CSF is clinically applicable and may be considered for future use in therapeutic measures for multiple sclerosis treatment.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Linfócitos T CD4-Positivos/efeitos dos fármacos
Encefalomielite Autoimune Experimental/tratamento farmacológico
Encefalomielite Autoimune Experimental/fisiopatologia
Fator Estimulador de Colônias de Granulócitos/uso terapêutico
Recuperação de Função Fisiológica/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Anexina A5/metabolismo
Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Citocinas/metabolismo
Modelos Animais de Doenças
Encefalomielite Autoimune Experimental/induzido quimicamente
Feminino
Adjuvante de Freund/toxicidade
Expressão Gênica/efeitos dos fármacos
Camundongos
Camundongos Endogâmicos C57BL
Glicoproteína Mielina-Oligodendrócito/toxicidade
Óxido Nítrico/metabolismo
Fragmentos de Peptídeos/toxicidade
Toxina Pertussis/toxicidade
Baço/patologia
Proteína X Associada a bcl-2/genética
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Annexin A5); 0 (Cytokines); 0 (Myelin-Oligodendrocyte Glycoprotein); 0 (Peptide Fragments); 0 (bcl-2-Associated X Protein); 0 (myelin oligodendrocyte glycoprotein (35-55)); 143011-72-7 (Granulocyte Colony-Stimulating Factor); 31C4KY9ESH (Nitric Oxide); 9007-81-2 (Freund's Adjuvant); EC 2.4.2.31 (Pertussis Toxin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:180218
[Lr] Data última revisão:
180218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  3 / 9823 MEDLINE  
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[PMID]:29287781
[Au] Autor:Cervantes-Llanos M; Lagumersindez-Denis N; Marín-Prida J; Pavón-Fuentes N; Falcon-Cama V; Piniella-Matamoros B; Camacho-Rodríguez H; Fernández-Massó JR; Valenzuela-Silva C; Raíces-Cruz I; Pentón-Arias E; Teixeira MM; Pentón-Rol G
[Ad] Endereço:Center for Genetic Engineering and Biotechnology (CIGB), Ave. 31 e/ 158 y 190, Cubanacán, Playa, Havana, PO Box 6162, Cuba.
[Ti] Título:Beneficial effects of oral administration of C-Phycocyanin and Phycocyanobilin in rodent models of experimental autoimmune encephalomyelitis.
[So] Source:Life Sci;194:130-138, 2018 Feb 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The only three oral treatments currently available for multiple sclerosis (MS) target the relapsing forms of the disease and concerns regarding efficacy, safety and tolerability limit their use. Identifying novel oral disease-modifying therapies for MS, targeting both its inflammatory and neurodegenerative components is still a major goal. AIM: The scope of this study was to provide evidence that the oral administration of C-Phycocyanin (C-PC), the main biliprotein of the Spirulina platensis cyanobacteria and its tetrapyrrolic prosthetic group, Phycocyanobilin (PCB), exert ameliorating actions on rodent models of experimental autoimmune encephalomyelitis (EAE). MAIN METHODS: EAE was induced in Lewis rats using the spinal cord encephalitogen from Sprague Dawley rats and in C57BL6 mice with MOG peptide. Clinical signs, motor function, oxidative stress markers, cytokine levels by ELISA and transmission electron microscopy analysis were assessed. KEY FINDINGS: Either prophylactic or early therapeutic administration of C-PC to Lewis rats with EAE, significantly improved clinical signs and restored the motor function of the animals. Furthermore, C-PC positively modulated oxidative stress markers measured in brain homogenate and serum and protected the integrity of cerebral myelin sheaths as shown by transmission electron microscopy analysis. In C57BL/6 mice with EAE, PCB orally improved clinical status of the animals and reduced the expression levels of brain IL-6 and IFN-γ proinflammatory cytokines. SIGNIFICANCE: These results, for the first time, support the fact that both C-PC and PCB administered orally could potentially improve neuroinflammation, protect from demyelination and axonal loss, which may be translated into an improved quality of life for MS patients.
[Mh] Termos MeSH primário: Encéfalo/efeitos dos fármacos
Encefalomielite Autoimune Experimental/tratamento farmacológico
Fármacos Neuroprotetores/uso terapêutico
Ficobilinas/uso terapêutico
Ficocianina/uso terapêutico
[Mh] Termos MeSH secundário: Administração Oral
Animais
Anti-Inflamatórios/administração & dosagem
Anti-Inflamatórios/química
Anti-Inflamatórios/uso terapêutico
Encéfalo/patologia
Citocinas/análise
Modelos Animais de Doenças
Encefalomielite Autoimune Experimental/patologia
Feminino
Interleucina-6/análise
Masculino
Camundongos Endogâmicos C57BL
Fármacos Neuroprotetores/administração & dosagem
Fármacos Neuroprotetores/química
Ficobilinas/administração & dosagem
Ficobilinas/química
Ficocianina/administração & dosagem
Ficocianina/química
Ratos Endogâmicos Lew
Ratos Sprague-Dawley
Spirulina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Cytokines); 0 (Interleukin-6); 0 (Neuroprotective Agents); 0 (Phycobilins); 11016-15-2 (Phycocyanin); 36NUT04V2K (phycocyanobilin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171231
[St] Status:MEDLINE


  4 / 9823 MEDLINE  
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[PMID]:28461106
[Au] Autor:Staun-Ram E; Miller A
[Ad] Endereço:Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
[Ti] Título:Effector and regulatory B cells in Multiple Sclerosis.
[So] Source:Clin Immunol;184:11-25, 2017 11.
[Is] ISSN:1521-7035
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The role of B cells in the pathogenesis of Multiple Sclerosis (MS), an autoimmune neurodegenerative disease, is becoming eminent in recent years, but the specific contribution of the distinct B cell subsets remains to be elucidated. Several B cell subsets have shown regulatory, anti-inflammatory capacities in response to stimuli in vitro, as well as in the animal model of MS: Experimental Autoimmune Encephalomyelitis (EAE). However, the functional role of the B regulatory cells (Bregs) in vivo and specifically in the human disease is yet to be clarified. In the present review, we have summarized the updated information on the roles of effector and regulatory B cells in MS and the immune-modulatory effects of MS therapeutic agents on their phenotype and function.
[Mh] Termos MeSH primário: Subpopulações de Linfócitos B/imunologia
Linfócitos B Reguladores/imunologia
Encefalomielite Autoimune Experimental/imunologia
Esclerose Múltipla/imunologia
[Mh] Termos MeSH secundário: Alemtuzumab/uso terapêutico
Animais
Crotonatos/uso terapêutico
Fumarato de Dimetilo/uso terapêutico
Cloridrato de Fingolimode/uso terapêutico
Acetato de Glatiramer/uso terapêutico
Seres Humanos
Fatores Imunológicos/uso terapêutico
Imunossupressores/uso terapêutico
Interferon beta/uso terapêutico
Esclerose Múltipla/tratamento farmacológico
Natalizumab/uso terapêutico
Rituximab/uso terapêutico
Toluidinas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Crotonates); 0 (Immunologic Factors); 0 (Immunosuppressive Agents); 0 (Natalizumab); 0 (Toluidines); 1C058IKG3B (teriflunomide); 3A189DH42V (Alemtuzumab); 4F4X42SYQ6 (Rituximab); 5M691HL4BO (Glatiramer Acetate); 77238-31-4 (Interferon-beta); FO2303MNI2 (Dimethyl Fumarate); G926EC510T (Fingolimod Hydrochloride)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  5 / 9823 MEDLINE  
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[PMID]:28468969
[Au] Autor:Gibson SA; Yang W; Yan Z; Liu Y; Rowse AL; Weinmann AS; Qin H; Benveniste EN
[Ad] Endereço:Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294; and.
[Ti] Título:Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation.
[So] Source:J Immunol;198(11):4244-4254, 2017 06 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many prosurvival and proinflammatory signaling pathways, including PI3K/Akt/mTOR and JAK/STAT. These pathways are essential for CD4 T cell activation and polarization, but little is known about how CK2 functions in T cells. In this article, we demonstrate that CK2 expression and kinase activity are induced upon CD4 T cell activation. Targeting the catalytic activity of CK2 using the next-generation small molecule inhibitor CX-4945 in vitro significantly and specifically inhibited mouse and human Th17 cell differentiation while promoting the generation of Foxp3 regulatory T cells (Tregs). These findings were associated with suppression of PI3K/Akt/mTOR activation and STAT3 phosphorylation upon CX-4945 treatment. Furthermore, we demonstrate that CX-4945 treatment inhibits the maturation of Th17 cells into inflammatory IFN-γ-coproducing effector cells. The Th17/Treg axis and maturation of Th17 cells are major contributing factors to the pathogenesis of many autoimmune disorders, including multiple sclerosis. Using a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, we demonstrate that in vivo administration of CX-4945 targets Akt/mTOR signaling in CD4 T cells and the Th17/Treg axis throughout disease. Importantly, CX-4945 treatment after disease initiation significantly reduced disease severity, which was associated with a significant decrease in the frequency of pathogenic IFN-γ and GM-CSF Th17 cells in the CNS. Our data implicate CK2 as a regulator of the Th17/Treg axis and Th17 cell maturation and suggest that CK2 could be targeted for the treatment of Th17 cell-driven autoimmune disorders.
[Mh] Termos MeSH primário: Caseína Quinase II/metabolismo
Linfócitos T Reguladores/imunologia
Células Th17/imunologia
[Mh] Termos MeSH secundário: Animais
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/metabolismo
Caseína Quinase II/antagonistas & inibidores
Caseína Quinase II/genética
Diferenciação Celular
Encefalomielite Autoimune Experimental/imunologia
Regulação da Expressão Gênica
Seres Humanos
Interferon gama/biossíntese
Interferon gama/imunologia
Ativação Linfocitária
Camundongos
Esclerose Múltipla/imunologia
Esclerose Múltipla/fisiopatologia
Naftiridinas/farmacologia
Fosfatidilinositol 3-Quinases/metabolismo
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais
Linfócitos T Reguladores/fisiologia
Células Th1/imunologia
Células Th17/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (5-(3-chlorophenylamino)benzo(c)(2,6)naphthyridine-8-carboxylic acid); 0 (Naphthyridines); 0 (STAT3 Transcription Factor); 0 (Stat3 protein, mouse); 82115-62-6 (Interferon-gamma); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (Pik3cd protein, mouse); EC 2.7.11.1 (Casein Kinase II); EC 2.7.11.1 (casein kinase 2, alpha, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180127
[Lr] Data última revisão:
180127
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601912


  6 / 9823 MEDLINE  
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[PMID]:29244457
[Au] Autor:Urakova MA; Bryndina IG
[Ti] Título:Water balance of lung and nitrogen oxide in blood at experimental autoimmune encephalomyelitis after capsaicin blockade of vagus nerve.
[So] Source:Patol Fiziol Eksp Ter;60(3):18-22, 2016 Jul-Sep.
[Is] ISSN:0031-2991
[Cp] País de publicação:Russia (Federation)
[La] Idioma:eng
[Ab] Resumo:The purpose of the research: To study the water balance of lung and NO level in blood in experimental autoimmune encephalomyelitis combined with capsaicin blockade of vagus nerve. Methods: Experiments were conducted on 47 adult (16-week-old) male rats weighing 220-280 g. To simulate the experimental autoimmune encephalomyelitis (EAE) rats were subcutaneously injected with encephalitogenic mixture in complete Freund's adjuvant (0.2 ml; the content of inactivated Mycobacterium tuberculosis was 5 mg/ml) at the rate of 100 mg of homologous spinal cord homogenate per animal. Сapsaicin blockade was performed by bilateral application of 50 uM capsaicin («Sigma¼) on the neck portions of vagus nerves. The animals were divided into 4 groups: intact rats - control group1; rats with EAE; rats with capsaicin application on vagus nerve + EAE; sham operated rats subjected to vagus nerves allocation without the subsequent capsaicin application + EAE - control group 2. The next parameters were detected: the content of nitric oxide in blood plasma; protein content in broncho-alveolar lavage fluid; lung water balance indices including the amount of total, extra- and intravascular fluid and blood supply of lungs, which were calculated based on wet and dry lung mass and the hemoglobin content in blood and lung tissue determined by hemiglobincyanide method. Results: It was found that EAE is accompanied by an increase of total fluid, extravascular fluid (EVF) and blood supply of lungs on the background of increasing content of nitric oxide in arterial (art) and venous (ven) blood. In EAE and its combination with bilateral capsaicin blockade of vagus nerve a strong negative correlation between the NOart / NOven coefficient and EVF amount was found out. The blockade of capsaicin-sensitive vagal afferents normalized lung water balance impaired in EAE and restored the levels of nitric oxide in blood plasma. Conclusion: The obtained results suggest that capsaicin-sensitive vagal afferents with NO-ergic mechanisms involvment take part in the development of pulmonary hyperhydration during experimental autoimmune encephalomyelitis.
[Mh] Termos MeSH primário: Capsaicina/efeitos adversos
Encefalomielite Autoimune Experimental
Pulmão
Óxidos de Nitrogênio
Nervo Vago
Equilíbrio Hidroeletrolítico
[Mh] Termos MeSH secundário: Animais
Capsaicina/farmacologia
Encefalomielite Autoimune Experimental/sangue
Encefalomielite Autoimune Experimental/imunologia
Pulmão/imunologia
Pulmão/metabolismo
Masculino
Óxidos de Nitrogênio/sangue
Óxidos de Nitrogênio/imunologia
Ratos
Equilíbrio Hidroeletrolítico/efeitos dos fármacos
Equilíbrio Hidroeletrolítico/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nitrogen Oxides); S07O44R1ZM (Capsaicin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


  7 / 9823 MEDLINE  
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[PMID]:27774592
[Au] Autor:Ma K; Chen X; Chen JC; Wang Y; Zhang XM; Huang F; Zheng JJ; Chen X; Yu W; Cheng KL; Feng YQ; Gu HY
[Ad] Endereço:Department of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
[Ti] Título:Rifampicin attenuates experimental autoimmune encephalomyelitis by inhibiting pathogenic Th17 cells responses.
[So] Source:J Neurochem;139(6):1151-1162, 2016 12.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Rifampicin, a broad-spectrum antibiotic, has neuroprotective, immunosuppressive, and anti-inflammatory properties. However, the effect of rifampicin on autoimmune disorders of the nervous system is not clear. In this study, we investigated whether rifampicin was beneficial to myelin oligodendrocyte glycoprotein peptide (MOG )-induced female C57BL/6 experimental autoimmune encephalomyelitis (EAE) mice, the well-established animal model of multiple sclerosis. Rifampicin treatment (daily from the first day after EAE immunization) remarkably attenuated clinical signs and loss of body weight, which are associated with suppression of inflammatory infiltration and demyelination in spinal cords of EAE mice. Furthermore, rifampicin dramatically reduced the disruption of blood-brain barrier integrity, down-regulated serum concentration of IL-6 and IL-17A, inhibited pathological Th17 cell differentiation, and modulated the expression of p-STAT3 and p-p65. These results suggest that rifampicin is effective for attenuating the clinical severity of EAE mice, which may be related to its inhibitive ability in differentiation of Th17 cell and secretion of its key effector molecule IL-17A via regulation of excessive activation of the key signaling molecules of JAK/STAT pathway. Our findings may be helpful for developing therapeutic and preventive strategies for multiple sclerosis.
[Mh] Termos MeSH primário: Encefalomielite Autoimune Experimental/tratamento farmacológico
Encefalomielite Autoimune Experimental/imunologia
Rifampina/uso terapêutico
Células Th17/efeitos dos fármacos
Células Th17/imunologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Relação Dose-Resposta a Droga
Feminino
Camundongos
Camundongos Endogâmicos C57BL
Distribuição Aleatória
Rifampina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.13871


  8 / 9823 MEDLINE  
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[PMID]:28931570
[Au] Autor:Madsen PM; Pinto M; Patel S; McCarthy S; Gao H; Taherian M; Karmally S; Pereira CV; Dvoriantchikova G; Ivanov D; Tanaka KF; Moraes CT; Brambilla R
[Ad] Endereço:The Miami Project To Cure Paralysis, Leonard M. Miller School of Medicine, University of Miami, Florida 33136.
[Ti] Título:Mitochondrial DNA Double-Strand Breaks in Oligodendrocytes Cause Demyelination, Axonal Injury, and CNS Inflammation.
[So] Source:J Neurosci;37(42):10185-10199, 2017 Oct 18.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitochondrial dysfunction has been implicated in the pathophysiology of neurodegenerative disorders, including multiple sclerosis (MS). To date, the investigation of mitochondrial dysfunction in MS has focused exclusively on neurons, with no studies exploring whether dysregulation of mitochondrial bioenergetics and/or genetics in oligodendrocytes might be associated with the etiopathogenesis of MS and other demyelinating syndromes. To address this question, we established a mouse model where mitochondrial DNA (mtDNA) double-strand breaks (DSBs) were specifically induced in myelinating oligodendrocytes (PLP:mtPstI mice) by expressing a mitochondrial-targeted endonuclease, mtPstI, starting at 3 weeks of age. In both female and male mice, DSBs of oligodendroglial mtDNA caused impairment of locomotor function, chronic demyelination, glial activation, and axonal degeneration, which became more severe with time of induction. In addition, after short transient induction of mtDNA DSBs, PLP:mtPstI mice showed an exacerbated response to experimental autoimmune encephalomyelitis. Together, our data demonstrate that mtDNA damage can cause primary oligodendropathy, which in turn triggers demyelination, proving PLP:mtPstI mice to be a useful tool to study the pathological consequences of mitochondrial dysfunction in oligodendrocytes. In addition, the demyelination and axonal loss displayed by PLP:mtPstI mice recapitulate some of the key features of chronic demyelinating syndromes, including progressive MS forms, which are not accurately reproduced in the models currently available. For this reason, the PLP:mtPstI mouse represents a unique and much needed platform for testing remyelinating therapies. In this study, we show that oligodendrocyte-specific mitochondrial DNA double-strand breaks in PLP:mtPstI mice cause oligodendrocyte death and demyelination associated with axonal damage and glial activation. Hence, PLP:mtPstI mice represent a unique tool to study the pathological consequences of mitochondrial dysfunction in oligodendrocytes, as well as an ideal platform to test remyelinating and neuroprotective agents.
[Mh] Termos MeSH primário: Axônios/patologia
Quebras de DNA de Cadeia Dupla
DNA Mitocondrial/genética
Doenças Desmielinizantes/genética
Doenças Desmielinizantes/patologia
Oligodendroglia/patologia
[Mh] Termos MeSH secundário: Animais
Sistema Nervoso Central/patologia
Sistema Nervoso Central/fisiologia
Encefalomielite Autoimune Experimental/genética
Encefalomielite Autoimune Experimental/patologia
Feminino
Inflamação/genética
Inflamação/patologia
Locomoção/fisiologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Degeneração Neural/genética
Degeneração Neural/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1378-17.2017


  9 / 9823 MEDLINE  
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[PMID]:28930663
[Au] Autor:Krasemann S; Madore C; Cialic R; Baufeld C; Calcagno N; El Fatimy R; Beckers L; O'Loughlin E; Xu Y; Fanek Z; Greco DJ; Smith ST; Tweet G; Humulock Z; Zrzavy T; Conde-Sanroman P; Gacias M; Weng Z; Chen H; Tjon E; Mazaheri F; Hartmann K; Madi A; Ulrich JD; Glatzel M; Worthmann A; Heeren J; Budnik B; Lemere C; Ikezu T; Heppner FL; Litvak V; Holtzman DM; Lassmann H; Weiner HL; Ochando J; Haass C; Butovsky O
[Ad] Endereço:Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
[Ti] Título:The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.
[So] Source:Immunity;47(3):566-581.e9, 2017 Sep 19.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic ß-amyloid (Aß)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
[Mh] Termos MeSH primário: Apolipoproteínas E/metabolismo
Glicoproteínas de Membrana/metabolismo
Microglia/metabolismo
Doenças Neurodegenerativas/genética
Doenças Neurodegenerativas/metabolismo
Receptores Imunológicos/metabolismo
Transdução de Sinais
Transcriptoma
[Mh] Termos MeSH secundário: Doença de Alzheimer/genética
Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Peptídeos beta-Amiloides/metabolismo
Precursor de Proteína beta-Amiloide/metabolismo
Animais
Apolipoproteínas E/deficiência
Apolipoproteínas E/genética
Apoptose/genética
Apoptose/imunologia
Córtex Cerebral/metabolismo
Córtex Cerebral/patologia
Análise por Conglomerados
Modelos Animais de Doenças
Encefalomielite Autoimune Experimental
Feminino
Perfilação da Expressão Gênica
Regulação da Expressão Gênica
Marcação de Genes
Seres Humanos
Tolerância Imunológica
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Microglia/imunologia
Monócitos/imunologia
Monócitos/metabolismo
Doenças Neurodegenerativas/imunologia
Neurônios/metabolismo
Fagocitose/genética
Fagocitose/imunologia
Fenótipo
Placa Amiloide/metabolismo
Placa Amiloide/patologia
Superóxido Dismutase-1/genética
Superóxido Dismutase-1/metabolismo
Fator de Crescimento Transformador beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Apolipoproteins E); 0 (Membrane Glycoproteins); 0 (Receptors, Immunologic); 0 (Transforming Growth Factor beta); 0 (Trem2 protein, mouse); EC 1.15.1.1 (Superoxide Dismutase-1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE


  10 / 9823 MEDLINE  
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[PMID]:28898256
[Au] Autor:Zhu H; Lemos H; Bhatt B; Islam BN; Singh A; Gurav A; Huang L; Browning DD; Mellor A; Fulzele S; Singh N
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States of America.
[Ti] Título:Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity.
[So] Source:PLoS One;12(9):e0183484, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Carbidopa is a drug that blocks conversion of levodopa to dopamine outside of central nervous system (CNS) and thus inhibits unwanted side effects of levodopa on organs located outside of CNS during management of Parkinson's Disease (PD). PD is associated with increased expression of inflammatory genes in peripheral and central nervous system (CNS), infiltration of immune cells into brain, and increased numbers of activated/memory T cells. Animal models of PD have shown a critical role of T cells in inducing pathology in CNS. However, the effect of carbidopa on T cell responses in vivo is unknown. In this report, we show that carbidopa strongly inhibited T cell activation in vitro and in vivo. Accordingly, carbidopa mitigated myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG-35-55) induced experimental autoimmune encephalitis (EAE) and collagen induced arthritis in animal models. The data presented here suggest that in addition to blocking peripheral conversion of levodopa, carbidopa may inhibit T cell responses in PD individuals and implicate a potential therapeutic use of carbidopa in suppression of T cell mediated pathologies.
[Mh] Termos MeSH primário: Antiparkinsonianos/farmacologia
Autoimunidade/efeitos dos fármacos
Carbidopa/farmacologia
Dopaminérgicos/farmacologia
Ativação Linfocitária/efeitos dos fármacos
Linfócitos T/efeitos dos fármacos
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Animais
Artrite Experimental/tratamento farmacológico
Artrite Experimental/imunologia
Artrite Experimental/metabolismo
Artrite Experimental/patologia
Doenças Autoimunes/imunologia
Doenças Autoimunes/metabolismo
Citocinas/metabolismo
Modelos Animais de Doenças
Encefalomielite Autoimune Experimental/tratamento farmacológico
Encefalomielite Autoimune Experimental/imunologia
Encefalomielite Autoimune Experimental/metabolismo
Mediadores da Inflamação/metabolismo
Ativação Linfocitária/imunologia
Contagem de Linfócitos
Macrófagos/efeitos dos fármacos
Macrófagos/imunologia
Macrófagos/metabolismo
Camundongos
Subpopulações de Linfócitos T/efeitos dos fármacos
Subpopulações de Linfócitos T/imunologia
Subpopulações de Linfócitos T/metabolismo
Linfócitos T/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiparkinson Agents); 0 (Cytokines); 0 (Dopamine Agents); 0 (Inflammation Mediators); MNX7R8C5VO (Carbidopa)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183484



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