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1.
Mol Neurobiol ; 57(12): 5263-5275, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32869183

RESUMO

Similar to its predecessors, coronavirus disease 2019 (COVID-19) exhibits neurotrophic properties, which lead to progression of neurologic sequelae. Besides direct viral invasion to the central nervous system (CNS), indirect CNS involvement through viral-mediated immune response is plausible. Aberrant immune pathways such as extreme release of cytokines (cytokine storm), autoimmunity mediated by cross-reactivity between CNS components and viral particles, and microglial activation propagate CNS damage in these patients. Here, we review the currently available evidence to discuss the plausible immunologic pathways that may contribute to the development of COVID-19 neurological complications, namely Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, Guillain-Barre syndrome, seizure, and brainstem involvement.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Doenças do Sistema Nervoso/etiologia , Pandemias , Pneumonia Viral/complicações , Animais , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Tronco Encefálico/fisiopatologia , Tronco Encefálico/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Efeito Citopatogênico Viral , Surtos de Doenças , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/imunologia , Humanos , Camundongos , Esclerose Múltipla/etiologia , Esclerose Múltipla/imunologia , Proteínas do Tecido Nervoso/fisiologia , Doenças do Sistema Nervoso/imunologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/imunologia , Neuroglia/patologia , Neuroglia/virologia , Neurônios/patologia , Neurônios/virologia , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/imunologia , Receptores Virais/fisiologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Convulsões/etiologia , Convulsões/imunologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/imunologia
2.
Am J Med ; 133(7): 783-788, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32259516

RESUMO

Multiple sclerosis (MS) is a common, severe neurological disease that affects millions of people worldwide. Nevertheless, the actual cause of MS remains unknown. Smoking has been studied with respect to MS development and progression. The objectives of this review were to examine the relationship between smoking and MS and to understand the possible molecular mechanisms underlying the association. PubMed was searched for articles related to the study topic published between 2012 and 2020 using the search terms "multiple sclerosis," "smoking," "risk factors," "cigarettes," and "molecular mechanisms." Studies show a significant relationship between smoking and the risk of MS. Furthermore, smoking has been linked to the progression of MS at the patient and population levels. However, the underlying mechanism remains to be explored in further studies; researchers still disagree on how the relationship between smoking and MS arises in different populations. Evidence from randomized controlled trials, systematic reviews, and epidemiological studies shows that smokers have a higher risk of developing MS and experiencing related adverse symptoms and complications.


Assuntos
Esclerose Múltipla/etiologia , Fumar/efeitos adversos , Progressão da Doença , Saúde Global , Humanos , Morbidade/tendências , Esclerose Múltipla/epidemiologia , Fatores de Risco
3.
Int J Nanomedicine ; 15: 17-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021162

RESUMO

Background: Honokiol has been reported to possess anti-inflammatory and neuroprotective activities. However, the poor aqueous solubility of honokiol limits its clinical application for systemic administration. Purpose: This study aims to develop a novel formulation of nanosome-encapsulated honokiol (NHNK) for intravenous therapy against mouse experimental autoimmune encephalomyelitis (EAE) that mimics human multiple sclerosis. Methods: Nanosomes and NHNK were prepared by using an ultra-high pressure homogenization (UHPH) method. Mice were treated with NHNK or empty nanosomes during the peak phase of EAE symptoms. Symptoms of EAE were monitored and samples of the spinal cord were obtained for histopathological examinations. Results: The stock of NHNK containing honokiol in the nanosome formulation, which showed the structure of single phospholipid bilayer membranes, was well formulated with the particle size of 48.0 ± 0.1 nm and the encapsulation efficiency 58.1 ± 4.2%. Intravenous administration of NHNK ameliorated the severity of EAE accompanied by a significant reduction of demyelination and inflammation in the spinal cord. Furthermore, NHNK decreased the number of IL-6+, Iba-1+TNF +, Iba-1+IL-12 p40+, and CD3+IFN-γ+ cells infiltrating the spinal cord. Conclusion: The UHPH method simplified the preparation of NHNK with uniformly distributed nanosize and high encapsulation efficiency. Intravenous administration of NHNK ameliorated the severity of EAE by suppressing the infiltration of activated microglia and Th1 cells into the spinal cord. Collectively, these results suggest that the formulation of NHNK is a prospective therapeutic approach for inflammatory CNS diseases, such as multiple sclerosis.


Assuntos
Compostos de Bifenilo/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Lignanas/administração & dosagem , Nanoestruturas/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Encefalomielite Autoimune Experimental/etiologia , Feminino , Injeções Intravenosas , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/etiologia , Mielite/tratamento farmacológico , Mielite/etiologia , Nanoestruturas/química , Fármacos Neuroprotetores/farmacologia , Medula Espinal/patologia , Células Th1/efeitos dos fármacos , Células Th1/patologia
4.
Genes (Basel) ; 11(1)2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31947683

RESUMO

Genome-wide association studies have identified more than 200 multiple sclerosis (MS)-associated loci across the human genome over the last decade, suggesting complexity in the disease etiology. This complexity poses at least two challenges: the definition of an etiological model including the impact of nongenetic factors, and the clinical translation of genomic data that may be drivers for new druggable targets. We reviewed studies dealing with single genes of interest, to understand how MS-associated single nucleotide polymorphism (SNP) variants affect the expression and the function of those genes. We then surveyed studies on the bioinformatic reworking of genome-wide association studies (GWAS) data, with aggregate analyses of many GWAS loci, each contributing with a small effect to the overall disease predisposition. These investigations uncovered new information, especially when combined with nongenetic factors having possible roles in the disease etiology. In this context, the interactome approach, defined as "modules of genes whose products are known to physically interact with environmental or human factors with plausible relevance for MS pathogenesis", will be reported in detail. For a future perspective, a polygenic risk score, defined as a cumulative risk derived from aggregating the contributions of many DNA variants associated with a complex trait, may be integrated with data on environmental factors affecting the disease risk or protection.


Assuntos
Interação Gene-Ambiente , Predisposição Genética para Doença , Genoma Humano , Esclerose Múltipla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estudo de Associação Genômica Ampla , Humanos , Esclerose Múltipla/etiologia , Esclerose Múltipla/genética
5.
J Neuroimmunol ; 338: 577107, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31726376

RESUMO

The role of damage-associated molecular patterns in multiple sclerosis (MS) is under investigation. Here, we studied the contribution of circulating high mobility group box protein 1 (HMGB1) and mitochondrial DNA (mtDNA) to neuroinflammation in progressive MS. We measured plasmatic mtDNA, HMGB1 and pro-inflammatory cytokines in 38 secondary progressive (SP) patients, 35 primary progressive (PP) patients and 42 controls. Free mtDNA was higher in SP than PP. Pro-inflammatory cytokines were increased in progressive patients. In PP, tumor necrosis factor-α correlated with MS Severity Score. Thus, in progressive patients, plasmatic mtDNA and pro-inflammatory cytokines likely contribute to the systemic inflammatory status.


Assuntos
Citocinas/sangue , DNA Mitocondrial/sangue , Esclerose Múltipla/etiologia , Adolescente , Adulto , Idoso , Feminino , Proteína HMGB1/sangue , Humanos , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
6.
PLoS One ; 14(12): e0226615, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31846493

RESUMO

BACKGROUND: Entropy is a thermodynamic variable statistically correlated with the disorder of a system. The hypothesis that entropy can be used to identify potentially unhealthy conditions was first suggested by Schrödinger, one of the founding fathers of quantum mechanics. Shannon later defined entropy as the quantity of information stored in a system. Shannon's entropy has the advantage of being adaptable across a variety of disciplines, including genetic studies on complex immunogenetic systems such as the human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) systems. METHODS: In our study, entropy associated to the HLA and KIR systems was compared between a cohort of 619 Sardinian healthy controls and a group of 270 patients affected by multiple sclerosis (MS), the latter stratified into 81 patients with primary progressive multiple sclerosis (PPMS) and 189 patients with relapsing remitting multiple sclerosis (RRMS). RESULTS: The entropy associated to HLA four-loci haplotypes (A, B, C, DR) and combinations of two inhibitory KIR genes was significantly higher in patients affected by RRMS than in healthy controls. No significant differences were observed for patients with PPMS. By calculating the total HLA and KIR entropy ratio in each subject, it was possible to determine the individual risk of developing MS, particularly RRMS. CONCLUSIONS: In addition to the standard statistical methods used to evaluate immunogenetic parameters associated to immune-mediated disease, the analysis of entropy measures the global disorder status deriving from these parameters. This innovative approach may represent a useful complementary tool to the risk assessment of immune-mediated disorders. Improved risk assessment is particularly important for family members of patients with MS. However, further investigation is warranted to confirm our findings and to evaluate the validity of the entropy-based method in other types of immune-mediated disorders.


Assuntos
Entropia , Doenças do Sistema Imunitário/etiologia , Modelos Teóricos , Esclerose Múltipla/diagnóstico , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Antígenos HLA/química , Antígenos HLA/genética , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/etiologia , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/etiologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/etiologia , Projetos Piloto , Receptores KIR/química , Receptores KIR/genética , Medição de Risco
7.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 30(6): 288-293, nov.-dic. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-186958

RESUMO

Introducción: La espasticidad representa un problema médico cuya incidencia está aumentando debido a enfermedades como parálisis cerebral, ictus, esclerosis múltiple, traumatismos o encefalopatías, afectando tanto a adultos como a niños. Los tratamientos incluyen rehabilitación, farmacoterapia y cirugía, entre las cuales destacamos las bombas de baclofeno intratecal. Material y métodos: Seleccionamos a los pacientes portadores de bomba de baclofeno intratecal implantada en el Hospital Clínico de Santiago de Compostela entre 2005-2018 y analizamos retrospectivamente los resultados mediante escalas de valoración de espasticidad, como la de Ashworth, así como las complicaciones observadas. Resultados: Se implantaron bombas de baclofeno a 17 pacientes, obteniendo una mejoría de 2 puntos en la escala de Ashworth en el 88,2% y de 1 punto en la escala de Penn en el 94%. Se observaron complicaciones en 3 pacientes. Conclusiones: El tratamiento con baclofeno intratecal es una técnica sencilla con resultados muy positivos para mejorar la calidad de vida de pacientes con espasticidad


Introduction: Spasticity represents a medical problem whose incidence is increasing during the last years due to pathologies such as cerebral palsy, stroke, multiple sclerosis, trauma or encephalopathy, affecting both adults and children. The treatments include rehabilitation, pharmacotherapy and surgery, among which we highlight intrathecal baclofen infusion devices. Material and methods: Intrathecal baclofen devices implanted patients in Clinical Hospital of Santiago de Compostela from 2005 to 2018 were selected for retrospective analysis using assessment of spasticity scales, such as Ashworth scale. Complications are described. Results: Surgery was performed in 17 patients for baclofen pump implant, achieving an improvement of 2 points on the Ashworth Scale in 88,2% of the patients and of 1 point on the Penn Scale in 94%. Complications were seen in 3 patients. Conclusions: Intrathecal baclofen is a simple technique with good results for improving the quality of life of patients with spasticity


Assuntos
Humanos , Masculino , Feminino , Adulto , Baclofeno/administração & dosagem , Espasticidade Muscular/tratamento farmacológico , Estudos Retrospectivos , Espasticidade Muscular/complicações , Esclerose Múltipla/etiologia , Neurofisiologia
8.
Semin Immunopathol ; 41(6): 711-726, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31732775

RESUMO

Multiple sclerosis (MS) is a frequent autoimmune demyelinating disease of the central nervous system (CNS). There are three clinical forms described: relapsing-remitting multiple sclerosis (RRMS), the most common initial presentation (85%) among which, if not treated, about half will transform, into the secondary progressive multiple sclerosis (SPMS) and the primary progressive MS (PPMS) (15%) that is directly progressive without superimposed clinical relapses. Inflammation is present in all subsets of MS. The relapsing/remitting form could represent itself a particular interest for the study of inflammation resolution even though it remains incomplete in MS. Successful resolution of acute inflammation is a highly regulated process and dependent on mechanisms engaged early in the inflammatory response that are scarcely studied in MS. Moreover, recent classes of disease-modifying treatment (DMTs) that are effective against RRMS act by re-establishing the inflammatory imbalance, taking advantage of the pre-existing endogenous suppressor. In this review, we will discuss the active role of regulatory immune cells in inflammation resolution as well as the role of tissue and non-hematopoietic cells as contributors to inflammation resolution. Finally, we will explore how DMTs, more specifically induction therapies, impact the resolution of inflammation during MS.


Assuntos
Suscetibilidade a Doenças , Inflamação/etiologia , Inflamação/metabolismo , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Animais , Biomarcadores , Gerenciamento Clínico , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação , Inflamação/patologia , Inflamação/terapia , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia
9.
Neurology ; 93(24): e2203-e2215, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31690681

RESUMO

OBJECTIVE: To determine risk factors for multiple sclerosis (MS) in immigrants and to compare MS risk in immigrants and long-term residents in Ontario, Canada. METHODS: We applied a validated algorithm to linked, population-based immigration and health claims data to identify incident cases of MS in immigrants and long-term residents between 1994 and 2016. We conducted 2 multivariable Cox proportional hazards regression analyses: 1 analysis limited to the immigrant cohort assessing potential risk factors for developing MS, and 1 analysis comparing MS risk between immigrants and matched long-term residents (1:3 match). RESULTS: We identified 2,304,302 immigrants for the immigrant-only analysis, of whom 1,526 (0.066%) developed MS. Risk was greatest in those <15 years old at landing (referent <15 years; 16-30 years: hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.63-0.85; 31-45 years: HR 0.55, 95% CI 0.47-0.64). Immigrants from the Middle East (HR 1.22, 95% CI 1.06-1.40) were at greater MS risk than immigrants from Western nations; all other regions had lower risk (p < 0.0001). The matched analysis included 2,207,751 immigrants and 6,362,169 long-term residents. Immigrants were less likely to develop MS than long-term residents (p < 0.0001), although this lower risk was attenuated with longer residence in Canada. CONCLUSIONS: MS incidence in immigrants to Ontario, Canada, varied widely by region of origin, with greatest risk seen in those from the Middle East. Longer residence in Canada was associated with increased risk, even with migration in adulthood, suggesting that environmental exposures into adulthood contribute to MS risk.


Assuntos
Emigrantes e Imigrantes , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/etiologia , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
10.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600882

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I-IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Mitocôndrias/metabolismo , Esclerose Múltipla/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/etiologia , Feminino , Camundongos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/etiologia , Músculo Esquelético/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença
11.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31574937

RESUMO

The transcription factor NURR1 is a constitutively active orphan receptor belonging to the steroid hormone receptor class NR4A. Although a genetic association between NURR1 and autoimmune inflammatory diseases has never emerged from genome-wide association studies (GWAS), alterations in the expression of NURR1 have been observed in various autoimmune diseases. Specifically, its role in autoimmune inflammatory diseases is mainly related to its capability to counteract inflammation. In fact, NURR1 exerts anti-inflammatory functions inhibiting the transcription of the molecules involved in proinflammatory pathways, not only in the peripheral blood compartment, but also in the cerebral parenchyma acting in microglial cells and astrocytes. In parallel, NURR1 has been also linked to dopamine-associated brain disorders, such as Parkinson's disease (PD) and schizophrenia, since it is involved in the development and in the maintenance of midbrain dopaminergic neurons (mDA). Considering its role in neuro- and systemic inflammatory processes, here we review the evidences supporting its contribution to multiple sclerosis (MS), a chronic inflammatory autoimmune disease affecting the central nervous system (CNS). To date, the specific role of NURR1 in MS is still debated and few authors have studied this topic. Here, we plan to clarify this issue analyzing the reported association between NURR1 and MS in human and murine model studies.


Assuntos
Suscetibilidade a Doenças , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Regulação da Expressão Gênica , Humanos , Camundongos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
12.
Medicine (Baltimore) ; 98(38): e17224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567981

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a common autoimmune disease of the central nervous system (CNS), and is associated with genetic factors. FOXP3 gene polymorphism has been reported as the risk factor for MS, however, previous studies have showed conflicting results. The purpose of this study is to investigate the association between FOXP3 gene polymorphism and the susceptibility to MS. METHODS: Pubmed, Embase, library of Cochrane, and Web of Science were used to search the eligible articles from January 1980 up to October 2018. The odds ratio (ORs) and its 95% confidence intervals (CI) were used to evaluate the strength of association. Allele model, homozygote model, heterozygote model, dominant model, and recessive model were used to evaluate the association between FOXP3 gene polymorphism and MS. RESULTS: A total of 5 studies contained 1276 MS patients and 1447 controls (for rs3761548) and 600 MS patients and 640 controls (for rs2232365) were enrolled in this meta-analysis. The association showed significant differences in allele and dominant model for rs3761548 polymorphism. In addition, a clear tendency to significance was detected in homozygote and recessive model for rs3761548 (P = .052). Subgroup analysis indicated a significant risk of MS in all genotype models but heterozygotes in Asians. CONCLUSION: FOXP3 gene polymorphism rs3761548 was associated with a higher MS risk, especially in Asians. This conclusion needs to be validated in more large samples and multiracial studies. LEVEL OF EVIDENCE: Level III diagnostic study.


Assuntos
Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Genes/genética , Humanos , Esclerose Múltipla/etiologia
13.
Cells ; 8(9)2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484353

RESUMO

Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to brain atrophy are poorly understood, partly due to the lack of appropriate animal models to study this aspect of the disease. The purpose of this study was to assess brain volumes and neuro-axonal degeneration after acute and chronic cuprizone-induced demyelination. C57BL/6 male mice were intoxicated with cuprizone for up to 12 weeks. Brain volume, as well as total numbers and densities of neurons, were determined using design-based stereology. After five weeks of cuprizone intoxication, despite severe demyelination, brain volumes were not altered at this time point. After 12 weeks of cuprizone intoxication, a significant volume reduction was found in the corpus callosum and diverse subcortical areas, particularly the internal capsule and the thalamus. Thalamic volume loss was accompanied by glucose hypermetabolism, analyzed by [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography. This study demonstrates region-specific brain atrophy of different subcortical brain regions after chronic cuprizone-induced demyelination. The chronic cuprizone demyelination model in male mice is, thus, a useful tool to study the underlying mechanisms of subcortical brain atrophy and to investigate the effectiveness of therapeutic interventions.


Assuntos
Encéfalo/patologia , Esclerose Múltipla/patologia , Animais , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Quelantes/toxicidade , Cuprizona/toxicidade , Fluordesoxiglucose F18 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/etiologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos
15.
Iran J Allergy Asthma Immunol ; 18(3): 230-250, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522431

RESUMO

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


Assuntos
Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Comunicação Celular , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Ligantes , Macrófagos/imunologia , Macrófagos/metabolismo , Microglia/imunologia , Microglia/metabolismo , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Bainha de Mielina/imunologia , Bainha de Mielina/metabolismo , Oligodendroglia/citologia , Oligodendroglia/imunologia , Oligodendroglia/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética
16.
Radiol Med ; 124(12): 1296-1303, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31435862

RESUMO

AIM: Our aim was to assess MRI findings in the acute phase of ON and their correlation with visual acuity at presentation, visual outcome (VO) and MS development, to analyze a possible correlation between lesions number and diagnosis, and to assess correlation between orbits MRI and OCT. MATERIALS AND METHODS: We retrospectively studied 37 patients, who presented to our Emergency Department with an ON first episode from January 2015 to January 2017. Patients underwent immediately a complete neuro-ophthalmological evaluation, blood test, CSF analysis. MRI of brain, orbits, cervical spine was executed within 7 days from ON onset. Brain MRI was classified as: normal, non-specific, suspected demyelination, lesions with dissemination in space and time. Optic nerves findings were localized in three sites (intra-orbital, canalicular and chiasmal) and classified as: normal, STIR- alteration, altered contrast enhancement. Patients underwent neuro-ophthalmological follow-up and MRI at 6 months to assess VO (complete recovery, partial recovery, deficit persistence). Another follow-up at 1 year was performed to identify MS or clinically isolated syndrome (CIS). RESULTS: 64.8% patients received a diagnosis of MS; 35% of CIS. Lesions of the optic nerve were found in 65.8%. We observed statistically significant correlation between brain MRI pattern and diagnosis and between lesions number and diagnosis. We observed a statistically significant correlation between orbital MRI pattern and optical coherence tomography (OCT) results. MRI brain findings correlate with development of MS. MRI brain features and lesions number can predict the risk of MS conversion.


Assuntos
Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Neurite Óptica/diagnóstico por imagem , Doença Aguda , Adulto , Técnicas de Diagnóstico Oftalmológico , Serviço Hospitalar de Emergência , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/etiologia , Nervo Óptico/diagnóstico por imagem , Neurite Óptica/tratamento farmacológico , Estudos Retrospectivos , Estatísticas não Paramétricas , Esteroides/uso terapêutico , Fatores de Tempo , Tomografia de Coerência Óptica , Acuidade Visual , Adulto Jovem
17.
Int J Mol Sci ; 20(16)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31409036

RESUMO

Astrocytes play a key role in demyelinating diseases, like multiple sclerosis (MS), although many of their functions remain unknown. The aim of this study was to investigate the impact of astrocyte depletion upon de- and remyelination, inflammation, axonal damage, and virus distribution in Theiler`s murine encephalomyelitis (TME). Groups of two to six glial fibrillary acidic protein (GFAP)-thymidine-kinase transgenic SJL mice and SJL wildtype mice were infected with TME virus (TMEV) or mock (vehicle only). Astrocyte depletion was induced by the intraperitoneal administration of ganciclovir during the early and late phase of TME. The animals were clinically investigated while using a scoring system and a rotarod performance test. Necropsies were performed at 46 and 77 days post infection. Cervical and thoracic spinal cord segments were investigated using hematoxylin and eosin (H&E), luxol fast blue-cresyl violet (LFB), immunohistochemistry targeting Amigo2, aquaporin 4, CD3, CD34, GFAP, ionized calcium-binding adapter molecule 1 (Iba1), myelin basic protein (MBP), non-phosphorylated neurofilaments (np-NF), periaxin, S100A10, TMEV, and immunoelectron microscopy. The astrocyte depleted mice showed a deterioration of clinical signs, a downregulation and disorganization of aquaporin 4 in perivascular astrocytes accompanied by vascular leakage. Furthermore, astrocyte depleted mice showed reduced inflammation and lower numbers of TMEV positive cells in the spinal cord. The present study indicates that astrocyte depletion in virus triggered CNS diseases contributes to a deterioration of clinical signs that are mediated by a dysfunction of perivascular astrocytes.


Assuntos
Astrócitos/patologia , Doenças Desmielinizantes/patologia , Inflamação/patologia , Esclerose Múltipla/patologia , Animais , Astrócitos/virologia , Infecções por Cardiovirus/complicações , Infecções por Cardiovirus/patologia , Infecções por Cardiovirus/virologia , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Feminino , Inflamação/complicações , Inflamação/virologia , Camundongos , Esclerose Múltipla/etiologia , Esclerose Múltipla/virologia , Theilovirus/isolamento & purificação
18.
Ann Clin Transl Neurol ; 6(9): 1905-1922, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31392849

RESUMO

Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro-inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene-environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make-ups. It is notable that several of these pro-inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory-mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.


Assuntos
Exposição Ambiental/efeitos adversos , Interação Gene-Ambiente , Predisposição Genética para Doença , Esclerose Múltipla/etiologia , Humanos , Esclerose Múltipla/genética , Fatores de Risco , Fumar/efeitos adversos
20.
Acta Neurol Scand ; 140(5): 328-335, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31291697

RESUMO

BACKGROUND: A rising trend for incidence of multiple sclerosis (MS) has been observed during the recent years in Iran. Several factors have been investigated as the reason, but socioeconomic determinants have been neglected. The present study aimed to investigate the relationship between Human Development Index (HDI), income and education and MS prevalence in the provinces of Iran. METHODS: The data used in this study were obtained from three sources: (a) National Registry of MS for MS prevalence data from 2006 to 2013, (b) Statistical Centre of Iran for demographic, income, and percentage of educated people data, and (c) some previous studies for HDI data. RESULTS: The findings showed high prevalence of MS in the provinces of Iran. Most patients were residents of provinces with a higher socioeconomic level. Significant relationships were found between the prevalence of MS and HDI, income and educational level (P = .002, P = .006, and P = .001, respectively). CONCLUSION: Socioeconomic determinants in Iran are different from those in many other countries. It seems that Iranian provinces with a higher socioeconomic level have higher prevalence of MS. Further studies in smaller scale are needed to better understand the relationship between socioeconomic determinants and MS prevalence in the provinces of Iran.


Assuntos
Esclerose Múltipla/epidemiologia , Fatores Socioeconômicos , Adulto , Feminino , Humanos , Renda , Irã (Geográfico)/epidemiologia , Masculino , Esclerose Múltipla/etiologia , Prevalência , Sistema de Registros
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