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1.
Rev. chil. nutr ; 46(3): 230-238, jun. 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1003699

RESUMO

ABSTRACT This study analyzed the profile of scientific production related to the nutritional aspects of the etiology and/or progress of Multiple Sclerosis (MS). We conducted an integrative review that analyzed 64 works published in English, Spanish or Portuguese between 2012 and 2017 on the relationship between nutrition and MS. There was a predominance of studies in humans (54.0%, n= 34) and randomized clinical trials (38.3%, n= 13). The association between vitamin D and etiology progression and/or development of disabilities resulting from MS was the most studied aspect (30.2%, n= 19), followed by studies that evaluated the importance of fat concentration and/or types for MS risk (22.2%, n= 14), and research that analyzed the role of antioxidant vitamins (19.0%; n= 12) in the disease development and/ or evolution. The study showed that most research involves small samples and that a healthy diet contributes to the prevention and mitigation of disease evolution. However, this affirmation cannot be made with regards to dietary supplements. Further research is necessary, from cross-sectional studies to randomized clinical trials considering the wide knowledge gap on this subject.


RESUMEN El presente estudio buscó plantear el perfil de las producciones científicas que relacionan aspectos nutricionales con la etiología y/o progresión de la Esclerosis Múltiple (EM). Fue una revisión integrativa que analizó 63 trabajos publicados en el idioma inglés, español y portugués, entre 2012 a 2017, sobre la relación entre los aspectos nutricionales y la EM. Predominaron estudios con seres humanos (54,0%, n= 34), del tipo ensayo clínico randomizado (38,3%, n= 13). La asociación de la vitamina D con la etiología, progresión y/o desarrollo de incapacidades consecuentes de la EM fue la más estudiada (30,2%, n= 19), seguida de los estudios que evaluaron la importancia de la concentración y/o de los tipos de gordura para el riesgo o progresión de la EM (22,2%, n= 14), y de estudios que analizaron el papel de las vitaminas antioxidantes (19,0%; n= 12) en el desencadenamiento y/o evolución de la enfermedad. La mayoría de los estudios incluyó muestras pequeñas y una dieta saludable que aporta con la prevención y atenuación de la evolución de la enfermedad. No se pueó hacer esta afirmación para los suplementos dietéticos. Son necesarios más estudios, dada la enorme laguna de conocimiento que envuelve el tema.


Assuntos
Humanos , Alimentação , Alimentos , Progressão da Doença , Esclerose Múltipla/etiologia , Literatura de Revisão como Assunto
3.
Saudi Med J ; 40(4): 372-378, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30957131

RESUMO

OBJECTIVES: To determine if there is a relationship between acute stress and either the onset or relapse of multiple sclerosis (MS) and to discover how different types of acute stressors may be involved. Methods:  This study was carried out in Saudi Arabia between September 2017 and June 2018 and involved King Fahad University Hospital in Eastern province, Arfa Multiple Sclerosis Society in the Central and Western province of Saudi Arabia. A cross-sectional descriptive study was performed using an Arabic self-constructed questionnaire consisted of 4 sections: 1) demographic data and time of diagnosis; 2) emotional/psychological stressors; 3) environmental/physical stressors; and 4) 4 specific stressors measuring their effect on the severity and recurrence of attacks. Results: A total of 370 patients participated in the study. Almost half of patients reported no effect of family problems on their disease, whereas the other reported that family problems have an impact on the onset or relapse of the disease. Majority of patients reported that work and social life stressors affect the recurrence of attacks. Cold weather showed no effect on MS; however, hot weather and physical activity increased the number of attacks. Continuous thinking about social stress and problems, mood swings, and sleep deprivation showed an impact on the severity and recurrence of attacks. Financial problems showed no effect.  Conclusion: Study indicates that an association exists between acute stress and relapse in MS but not the disease onset.


Assuntos
Esclerose Múltipla/epidemiologia , Esclerose Múltipla/etiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/complicações , Doença Aguda , Adolescente , Adulto , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Prevalência , Recidiva , Fatores de Risco , Arábia Saudita/epidemiologia , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Adulto Jovem
4.
Int J Mol Sci ; 20(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901861

RESUMO

Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults leading to severe disability. Besides genetic traits, environmental factors contribute to MS pathogenesis. Cigarette smoking increases the risk of MS in an HLA-dependent fashion, but the underlying mechanisms remain unknown. Here, we explored the effect of cigarette smoke exposure on spontaneous and induced models of experimental autoimmune encephalomyelitis (EAE) by evaluating clinical disease and, when relevant, blood leukocytes and histopathology. In the relapsing-remitting (RR) transgenic model in SJL/J mice, we observed very low incidence in both smoke-exposed and control groups. In the optico-spinal encephalomyelitis (OSE) double transgenic model in C57BL/6 mice, the early onset of EAE prevented a meaningful evaluation of the effects of cigarette smoke. In EAE models induced by immunization, daily exposure to cigarette smoke caused a delayed onset of EAE followed by a protracted disease course in SJL/J mice. In contrast, cigarette smoke exposure ameliorated the EAE clinical score in C57BL/6J mice. Our exploratory studies therefore show that genetic background influences the effects of cigarette smoke on autoimmune neuroinflammation. Importantly, our findings expose the challenge of identifying an animal model for studying the influence of cigarette smoke in MS.


Assuntos
Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/etiologia , Patrimônio Genético , Fumar/efeitos adversos , Idade de Início , Animais , Biópsia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/metabolismo , Imuno-Histoquímica , Camundongos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Fenótipo , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Medula Espinal/metabolismo , Medula Espinal/patologia
5.
J Neuroinflammation ; 16(1): 59, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30857557

RESUMO

BACKGROUND: Long-term outcome in multiple sclerosis (MS) depends on early treatment. In patients with acute optic neuritis (ON), an early inflammatory event, we investigated markers in cerebrospinal fluid (CSF), which may predict a diagnosis of MS. METHODS: Forty patients with acute ON were recruited in a prospective population-based cohort with median 29 months (range 19-41) of follow-up. Paired CSF and serum samples were taken within 14 days (range 2-38), prior to treatment. Prospectively, 16/40 patients were by a uniform algorithm diagnosed with MS (MS-ON) and 24 patients continued to manifest isolated ON (ION) during follow-up. Levels of cytokines and neurofilament light chain (NF-L) were measured at the onset of acute ON and compared to healthy controls (HC). Significance levels were corrected for multiple comparisons ("q"). The predictive value of biomarkers was determined with multivariable prediction models using nomograms. RESULTS: CSF TNF-α, IL-10, and CXCL13 levels were increased in MS-ON compared to those in ION patients (q = 0.021, 0.004, and 0.0006, respectively). MS-ON patients had increased CSF pleocytosis, IgG indices, and oligoclonal bands (OCBs) compared to ION (q = 0.0007, q = 0.0058, and q = 0.0021, respectively). CSF levels of IL-10, TNF-a, IL-17A, and CXCL13 in MS-ON patients correlated with leukocyte counts (r > 0.69 and p < 0.002) and IgG index (r > 0.55, p < 0.037). CSF NF-L levels were increased in ON patients compared to those in HC (q = 0.0077). In MS-ON, a progressive increase in NF-L levels was observed at 7 to 14 days after disease onset (r = 0.73, p < 0.0065). Receiver-operating characteristic (ROC) curves for two multivariable prediction models were generated, with IL-10, CXCL13, and NF-L in one ("candidate") and IgG index, OCB, and leukocytes in another ("routine"). Area under the curve was 0.89 [95% CI 0.77-1] and 0.86 [0.74-0.98], respectively. Predictions of the risk of MS diagnosis were illustrated by two nomograms. CONCLUSIONS: CSF TNF-α, IL-10, CXCL13, and NF-L levels were associated with the development of MS, suggesting that the inflammatory and neurodegenerative processes occurred early. Based on subsequent diagnosis, we observed a high predictive value of routine and candidate biomarkers in CSF for the development of MS in acute ON. The nomogram predictions may be useful in the diagnostic work-up of MS.


Assuntos
Citocinas/líquido cefalorraquidiano , Progressão da Doença , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/etiologia , Neurite Óptica/complicações , Adolescente , Adulto , Idoso , Quimiocinas CXC/líquido cefalorraquidiano , Estudos de Coortes , Planejamento em Saúde Comunitária , Feminino , Humanos , Interleucina-10/líquido cefalorraquidiano , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Bandas Oligoclonais/líquido cefalorraquidiano , Valor Preditivo dos Testes , Curva ROC , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Adulto Jovem
6.
Amino Acids ; 51(5): 745-759, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887124

RESUMO

It is well recognized that variation in the geographical distribution of prevalence of multiple sclerosis (MS) exists: increasing the latitude its prevalence increases as well, but the underlying causes of such dissimilarity still remained elusive as of today. Currently, the most accredited hypothesis is that the closer to the equator the more pronounced is the amount of sunlight which, in turn, increases the production of vitamin D. Cholecalciferol is indeed deficient in MS patients, but this factor does not explain by itself the etiopathogenesis of the disease. In the present study, to search for a pattern and provide a model of the disease's etiology consistent with this regional factor, as well with its changing ethnic, sex-ratio, lifestyle variations and the other unexplained aspects of MS, an extensive analysis of peer-reviewed literature and data was conducted. The arisen hypothesis was that, increasing the latitude, the factor that varies and can have the stronger effect on the human organism, is the continuous and ever-increasing diversity of the natural light-dark cycle. The consequent effort of the suprachiasmatic nucleus to entrain the organism's circadian rhythm affects the hypothalamic-pituitary-adrenal axis resulting in desynchronizing the central and peripheral circadian clocks and pathologizing the immunitary system. To verify such hypothesis, a theoretical framework of the etiopathogenesis, coherent with the gathered literature, was conceived and a demonstration to corroborate it was eventually devised and performed. The results underscored that people living in countries subjected to a further circadian disruptive factor, as daylight saving time, have a 6.35 times higher prevalence of MS than States placed on their same latitude that do not observe it, thus strongly supporting the hypothesis. As further reinforcement of the conclusions, it is worth mentioning that the levels of polyamines rise abruptly in autoimmune diseases. Moreover, among their numerous roles, these polycations participate to the regulation of the circadian clock so their sudden variation might disrupt it. Following these interesting findings, new perspectives in therapies are, therefore, proposed.


Assuntos
Ritmo Circadiano , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Animais , Humanos , Esclerose Múltipla/etiologia
7.
Med Sci Monit ; 25: 893-902, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30703074

RESUMO

Multiple sclerosis (MS) is a chronic immune-mediated disease of the spinal cord and brain. Many studies have shown that smoking and passive smoking are key environmental risk factors for MS. Here, we provide an overview of the human leukocyte antigen (HLA) gene studies on smoking and MS risk, and we discuss recent studies on between epigenetics and smoking-induced MS. In addition, in this review we also summarize current research advances in biological pathways and smoking-induced MS. This review provides an overview of studies on the association between smoking, passive smoking, and MS susceptibility, and the underlying molecular mechanism.


Assuntos
Fumar Cigarros/efeitos adversos , Esclerose Múltipla/etiologia , Poluição por Fumaça de Tabaco/efeitos adversos , China , Epigênese Genética/genética , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Humanos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Fatores de Risco , Fumar/efeitos adversos
8.
Nutrients ; 11(2)2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30781687

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a multifactorial disease with unknown etiology. It is assumed to result from interplay between genetic and environmental factors, including nutrition. We hypothesized that there are differences in nutritional parameters between MS patients and healthy controls. METHODS: We examined 63 MS patients and 83 healthy controls. Nutritional status was determined by a dietary questionnaire, blood tests, quantification of cell membrane fatty acids, and serum antioxidant capacity. RESULTS: We found that MS patients consumed a more limited diet compared with the healthy group, indicated by a lower average of 31 nutrients and by consumption levels of zinc and thiamine below the recommended daily intake. Both consumption and measured iron values were significantly lower in MS patients, with the lowest measures in the severe MS group. Long saturated fatty acids (>C16) were significantly lower in MS patients, while palmitic and palmitoleic acids were both higher. Serum total antioxidant capacity was significantly lower in the MS group compared with healthy controls, with the lowest measures in patients with severe MS. CONCLUSIONS: This study points to a possible correlation between nutritional status and MS. Understanding the clinical meaning of these findings will potentially allow for the development of future personalized dietary interventions as part of MS treatment.


Assuntos
Antioxidantes/análise , Dieta/efeitos adversos , Esclerose Múltipla/sangue , Estado Nutricional , Adulto , Estudos de Casos e Controles , Inquéritos sobre Dietas , Ingestão de Alimentos , Ácidos Graxos/análise , Feminino , Humanos , Ferro/análise , Masculino , Esclerose Múltipla/etiologia , Recomendações Nutricionais , Tiamina/análise , Zinco/análise
9.
Int J Mol Sci ; 20(2)2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30669615

RESUMO

Theiler's murine encephalomyelitis virus (TMEV), a naturally occurring, enteric pathogen of mice is a Cardiovirus of the Picornaviridae family. Low neurovirulent TMEV strains such as BeAn cause a severe demyelinating disease in susceptible SJL mice following intracerebral infection. Furthermore, TMEV infections of C57BL/6 mice cause acute polioencephalitis initiating a process of epileptogenesis that results in spontaneous recurrent epileptic seizures in approximately 50% of affected mice. Moreover, C3H mice develop cardiac lesions after an intraperitoneal high-dose application of TMEV. Consequently, TMEV-induced diseases are widely used as animal models for multiple sclerosis, epilepsy, and myocarditis. The present review summarizes morphological lesions and pathogenic mechanisms triggered by TMEV with a special focus on the development of hippocampal degeneration and seizures in C57BL/6 mice as well as demyelination in the spinal cord in SJL mice. Furthermore, a detailed description of innate and adaptive immune responses is given. TMEV studies provide novel insights into the complexity of organ- and mouse strain-specific immunopathology and help to identify factors critical for virus persistence.


Assuntos
Doenças dos Animais/virologia , Infecções por Cardiovirus/veterinária , Theilovirus/fisiologia , Imunidade Adaptativa , Doenças dos Animais/imunologia , Doenças dos Animais/patologia , Doenças dos Animais/transmissão , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epilepsia/etiologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Humanos , Imunidade Inata , Camundongos , Esclerose Múltipla/etiologia , Esclerose Múltipla/patologia , Miocardite/etiologia , Miocardite/patologia , Miocardite/fisiopatologia , Convulsões/etiologia , Convulsões/patologia , Convulsões/fisiopatologia , Tropismo Viral
10.
Neuron ; 101(4): 615-624.e5, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30686733

RESUMO

Axon loss determines persistent disability in multiple sclerosis patients. Here, we use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival. We rule out the endoplasmic reticulum, glutamate excitotoxicity, and the reversal of the sodium-calcium exchanger as sources of intra-axonal calcium accumulation and instead identify nanoscale ruptures of the axonal plasma membrane as the critical path of calcium entry.


Assuntos
Axônios/metabolismo , Cálcio/metabolismo , Membrana Celular/patologia , Esclerose Múltipla/metabolismo , Animais , Axônios/patologia , Membrana Celular/metabolismo , Feminino , Transporte de Íons , Masculino , Camundongos , Esclerose Múltipla/etiologia
11.
Mult Scler Relat Disord ; 24: 157-174, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30015080

RESUMO

Multiple Sclerosis is a chronic, progressive and debilitating neurological disease which, despite extensive study for over 100 years, remains of enigmatic aetiology. Drawn from the epidemiological evidence, there exists a consensus that there are environmental (possibly infectious) factors that contribute to disease pathogenesis that have not yet been fully elucidated. Here we propose a three-tiered hypothesis: 1) a clinic-epidemiological model of multiple sclerosis as a rare late complication of two sequential infections (with the temporal sequence of infections being important); 2) a proposal that the first event is helminthic infection with Enterobius Vermicularis, and the second is Epstein Barr Virus infection; and 3) a proposal for a testable biological mechanism, involving T-Cell exhaustion for Epstein-Barr Virus protein LMP2A. We believe that this model satisfies some of the as-yet unexplained features of multiple sclerosis epidemiology, is consistent with the clinical and neuropathological features of the disease and is potentially testable by experiment. This model may be generalizable to other autoimmune diseases.


Assuntos
Modelos Neurológicos , Esclerose Múltipla/etiologia , Esclerose Múltipla/genética , Enterobíase/complicações , Enterobíase/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/virologia , Linfócitos T/imunologia , Linfócitos T/virologia , Proteínas Virais/metabolismo
12.
Proc Natl Acad Sci U S A ; 115(21): 5528-5533, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29728463

RESUMO

Although immune attack against central nervous system (CNS) myelin is a central feature of multiple sclerosis (MS), its root cause is unresolved. In this report, we provide direct evidence that subtle biochemical modifications to brain myelin elicit pathological immune responses with radiological and histological properties similar to MS lesions. A subtle myelinopathy induced by abbreviated cuprizone treatment, coupled with subsequent immune stimulation, resulted in lesions of inflammatory demyelination. The degree of myelin injury dictated the resulting immune response; biochemical damage that was too limited or too extensive failed to trigger overt pathology. An inhibitor of peptidyl arginine deiminases (PADs), enzymes that alter myelin structure and correlate with MS lesion severity, mitigated pathology even when administered only during the myelin-altering phase. Moreover, cultured splenocytes were reactive against donor myelin isolates, a response that was substantially muted when splenocytes were exposed to myelin from donors treated with PAD inhibitors. By showing that a primary biochemical myelinopathy can trigger secondary pathological inflammation, "cuprizone autoimmune encephalitis" potentially reconciles conflicting theories about MS pathogenesis and provides a strong rationale for investigating myelin as a primary target for early, preventative therapy.


Assuntos
Doenças Desmielinizantes/etiologia , Modelos Animais de Doenças , Encefalite/patologia , Doença de Hashimoto/patologia , Inflamação/patologia , Esclerose Múltipla/etiologia , Bainha de Mielina/patologia , Animais , Cuprizona/toxicidade , Doenças Desmielinizantes/patologia , Encefalite/induzido quimicamente , Encefalite/imunologia , Doença de Hashimoto/induzido quimicamente , Doença de Hashimoto/imunologia , Humanos , Hidrolases/genética , Hidrolases/metabolismo , Inflamação/induzido quimicamente , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Monoaminoxidase/toxicidade , Esclerose Múltipla/patologia , Bainha de Mielina/imunologia , Bainha de Mielina/metabolismo
13.
Vaccine ; 36(23): 3208-3220, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29706295

RESUMO

Chronic inflammatory autoimmune diseases leading to target tissue destruction and disability are not only causing increase in patients' suffering but also contribute to huge economic burden for the society. General increase in life expectancy and high prevalence of these diseases both in elderly and younger population emphasize the importance of developing safe and effective vaccines. In this review, at first the possible mechanisms and risk factors associated with chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) are discussed. Current advances in the development of vaccines for such autoimmune diseases, particularly those based on DNA, altered peptide ligands and peptide loaded MHC II complexes are discussed in detail. Finally, strategies for improving the efficacy of potential vaccines are explored.


Assuntos
Doenças Autoimunes/prevenção & controle , Vacinas/farmacologia , Adjuvantes Imunológicos/farmacologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/prevenção & controle , Doenças Autoimunes/imunologia , Doença Crônica , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/prevenção & controle , Epitopos , Feminino , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Masculino , Esclerose Múltipla/etiologia , Esclerose Múltipla/prevenção & controle , Fatores Sexuais , Vacinas/administração & dosagem , Vacinas de DNA/farmacologia
14.
Med Hypotheses ; 115: 87-93, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29685206

RESUMO

Multiple sclerosis (MS) is a demyelinating disease which characteristically shows repeated relapses and remissions irregularly in the central nervous system. At present, the pathological mechanism of MS is unknown and we do not have any theories or mathematical models to explain its disseminated patterns in time and space. In this paper, we present a new theoretical model from a viewpoint of complex system with chaos model to reproduce and explain the non-linear clinical and pathological manifestations in MS. First, we adopted a discrete logistic equation with non-linear dynamics to prepare a scalar quantity for the strength of pathogenic factor at a specific location of the central nervous system at a specific time to reflect the negative feedback in immunity. Then, we set distinct minimum thresholds in the above-mentioned scalar quantity for demyelination possibly causing clinical relapses and for cerebral atrophy. With this simple model, we could theoretically reproduce all the subtypes of relapsing-remitting MS, primary progressive MS, and secondary progressive MS. With the sensitivity to initial conditions and sensitivity to minute change in parameters of the chaos theory, we could also reproduce the spatial dissemination. Such chaotic behavior could be reproduced with other similar upward-convex functions with appropriate set of initial conditions and parameters. In conclusion, by applying chaos theory to the three-dimensional scalar field of the central nervous system, we can reproduce the non-linear outcome of the clinical course and explain the unsolved disseminations in time and space of the MS patients.


Assuntos
Modelos Biológicos , Esclerose Múltipla/etiologia , Atrofia/patologia , Encéfalo/patologia , Humanos , Modelos Logísticos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Esclerose Múltipla Recidivante-Remitente/etiologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia , Dinâmica não Linear
15.
Int J Mol Sci ; 19(3)2018 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-29533975

RESUMO

In physiological conditions, different types of macrophages can be found within the central nervous system (CNS), i.e., microglia, meningeal macrophages, and perivascular (blood-brain barrier) and choroid plexus (blood-cerebrospinal fluid barrier) macrophages. Microglia and tissue-resident macrophages, as well as blood-borne monocytes, have different origins, as the former derive from yolk sac erythromyeloid precursors and the latter from the fetal liver or bone marrow. Accordingly, specific phenotypic patterns characterize each population. These cells function to maintain homeostasis and are directly involved in the development and resolution of neuroinflammatory processes. Also, following inflammation, circulating monocytes can be recruited and enter the CNS, therefore contributing to brain pathology. These cell populations have now been identified as key players in CNS pathology, including autoimmune diseases, such as multiple sclerosis, and degenerative diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer's disease. Here, we review the evidence on the involvement of CNS macrophages in neuroinflammation and the advantages, pitfalls, and translational opportunities of pharmacological interventions targeting these heterogeneous cellular populations for the treatment of brain diseases.


Assuntos
Doença de Alzheimer/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Macrófagos/metabolismo , Esclerose Múltipla/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/etiologia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Humanos , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/etiologia
16.
Mult Scler Relat Disord ; 20: 178-180, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29414294

RESUMO

A 51-year old woman with stage III melanoma participated in a phase II clinical trial in which she received subcutaneous rhGM-CSF injections for 3 years. She was in remission by the end of the trial. Seven months after discontinuing GM-CSF she had her first MS event. The unique timeline of rh-GM-CSF injections in a melanoma trial, during which yearly MRI scans showed subtle stable demyelination followed by RRMS onset shortly after discontinuation of treatment, may provide some insight on the role of GM-CSF in MS.


Assuntos
Antineoplásicos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Melanoma/tratamento farmacológico , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/etiologia , Antineoplásicos/uso terapêutico , Encéfalo/diagnóstico por imagem , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Coxa da Perna
17.
J Pharmacol Sci ; 136(2): 93-96, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29409686

RESUMO

Lysophosphatidic acid (LPA) and LPA1 receptor signaling play a crucial role in the initiation of peripheral nerve injury-induced neuropathic pain through the alternation of pain-related genes/proteins expression and demyelination. However, LPA and its signaling in the brain are still poorly understood. In the present study, we revealed that the LPA5 receptor expression in corpus callosum elevated after the initiation of demyelination, and the hyperalgesia through Aδ-fibers following cuprizone-induced demyelination was mediated by LPA5 signaling. These data suggest that LPA5 signaling may play a key role in the mechanisms underlying neuropathic pain following demyelination in the brain.


Assuntos
Cuprizona/efeitos adversos , Modelos Animais de Doenças , Esclerose Múltipla/etiologia , Esclerose Múltipla/genética , Neuralgia/etiologia , Neuralgia/genética , Receptores de Ácidos Lisofosfatídicos/fisiologia , Transdução de Sinais/fisiologia , Animais , Corpo Caloso/metabolismo , Feminino , Expressão Gênica , Lisofosfolipídeos/fisiologia , Masculino , Camundongos Endogâmicos , Esclerose Múltipla/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo
19.
Sci Rep ; 8(1): 259, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29321652

RESUMO

The innate immune system plays a central role in the immune-mediated pathology of multiple sclerosis, and is a therapeutic target for progressive disease. Recently, it has been demonstrated that MIS416, a novel immunomodulatory microparticle that activates NOD-2 and TLR-9-signaling, has disease-modifying activity in multiple sclerosis models. This activity is dependent on innate IFN-γ; however, the precise immune regulatory mechanisms amplified by MIS416 have not previously been determined. Using the experimental autoimmune encephalomyelitis model, MIS416 treatment was associated with IFN-γ-dependant expansion of Treg number and increased suppressive function; however, these cells did not account for disease reduction. Additionally, MIS416 treatment stimulated increased nitric oxide production that was IFN-γ-dependant but dispensable for protection. Finally, MIS416-mediated protection was shown to correlate with IFN-γ-dependant expansion of PDL-1-expressing peripheral myeloid cells, a subset of which was found to be selectively recruited to the brain. This central nervous system trafficking was independent of neuro-inflammatory signals as it occurred in MIS416-treated healthy mice. Together, these findings provide insight into regulatory myeloid cell activities amplified by MIS416-mediated NOD-2 and TLR-9 signalling and highlight the potential importance of these cells in accessing the brain where they may act locally and contribute to the control of neuroinflammation.


Assuntos
Antígeno B7-H1/genética , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Regulação da Expressão Gênica , Imunidade Inata , Interferon gama/metabolismo , Mielopoese , Animais , Antígeno B7-H1/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Feminino , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Mielopoese/genética , Mielopoese/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
20.
Rev Neurosci ; 29(1): 39-53, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28822986

RESUMO

Demyelinating diseases, such as multiple sclerosis (MS), are kinds of common diseases in the central nervous system (CNS), and originated from myelin loss and axonal damage. Oligodendrocyte dysfunction is the direct reason of demyelinating lesions in the CNS. Nitric oxide (NO) plays an important role in the pathological process of demyelinating diseases. Although the neurotoxicity of NO is more likely mediated by peroxynitrite rather than NO itself, NO can impair oligodendrocyte energy metabolism through mediating the damaging of mitochondrial DNA, mitochondrial membrane and mitochondrial respiratory chain complexes. In the progression of MS, NO can mainly mediate demyelination, axonal degeneration and cell death. Hence, in this review, we extensively discuss endangerments of NO in oligodendrocytes (OLs), which is suggested to be the main mediator in demyelinating diseases, e.g. MS. We hypothesize that NO takes part in MS through impairing the function of monocarboxylate transporter 1, especially causing axonal degeneration. Then, it further provides a new insight that NO for OLs may be a reliable therapeutic target to ameliorate the course of demyelinating diseases.


Assuntos
Doenças Mitocondriais/induzido quimicamente , Esclerose Múltipla/etiologia , Óxido Nítrico/toxicidade , Oligodendroglia/efeitos dos fármacos , Animais , Humanos , Esclerose Múltipla/metabolismo , Bainha de Mielina/patologia
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