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1.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804243

RESUMEN

A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple sclerosis (MS), stroke and traumatic brain injury (TBI), which are three of the most prevalent demyelinating disorders. Thanks to the properties described for CBD and its interesting profile in humans, both the phytocannabinoid and derivatives could be considered as potential candidates for clinical use. In this review we will summarize current advances in the use of CBD and other cannabinoids as future potential treatments. While new research is accelerating the process for the generation of novel drug candidates and identification of druggable targets, the collaboration of key players such as basic researchers, clinicians and pharmaceutical companies is required to bring novel therapies to the patients.


Asunto(s)
Cannabidiol/uso terapéutico , Cannabinoides/uso terapéutico , Cannabis/química , Enfermedades Desmielinizantes/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/patología , Enfermedades Desmielinizantes/patología , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología
2.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805762

RESUMEN

Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX's effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis.


Asunto(s)
Linfocitos B/patología , Encefalomielitis Autoinmune Experimental/patología , Toxina del Pertussis/administración & dosificación , Células Th17/patología , Traslado Adoptivo/métodos , Animales , Linfocitos B/inmunología , Movimiento Celular/inmunología , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Índice de Severidad de la Enfermedad , Células Th17/inmunología , Células Th17/trasplante
3.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805769

RESUMEN

Although the causes of Multiple Sclerosis (MS) still remain largely unknown, multiple lines of evidence suggest that Epstein-Barr virus (EBV) infection may contribute to the development of MS. Here, we aimed to identify the potential contribution of EBV-encoded and host cellular miRNAs to MS pathogenesis. We identified differentially expressed host miRNAs in EBV infected B cells (LCLs) and putative host/EBV miRNA interactions with MS risk loci. We estimated the genotype effect of MS risk loci on the identified putative miRNA:mRNA interactions in silico. We found that the protective allele of MS risk SNP rs4808760 reduces the expression of hsa-mir-3188-3p. In addition, our analysis suggests that hsa-let-7b-5p may interact with ZC3HAV1 differently in LCLs compared to B cells. In vitro assays indicated that the protective allele of MS risk SNP rs10271373 increases ZC3HAV1 expression in LCLs, but not in B cells. The higher expression for the protective allele in LCLs is consistent with increased IFN response via ZC3HAV1 and so decreased immune evasion by EBV. Taken together, this provides evidence that EBV infection dysregulates the B cell miRNA machinery, including MS risk miRNAs, which may contribute to MS pathogenesis via interaction with MS risk genes either directly or indirectly.


Asunto(s)
Linfocitos B/virología , Sitios Genéticos , Interacciones Huésped-Patógeno/genética , MicroARNs/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Alelos , Linfocitos B/inmunología , Secuencia de Bases , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , MicroARNs/inmunología , Modelos Biológicos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Esclerosis Múltiple/virología , Polimorfismo de Nucleótido Simple , Cultivo Primario de Células , ARN Mensajero/inmunología , Proteínas de Unión al ARN/inmunología , Transducción de Señal
4.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809077

RESUMEN

Pregnancy is a unique situation of physiological immunomodulation, as well as a strong Multiple Sclerosis (MS) disease modulator whose mechanisms are still unclear. Both maternal (decidua) and fetal (trophoblast) placental cells secrete extracellular vesicles (EVs), which are known to mediate cellular communication and modulate the maternal immune response. Their contribution to the MS disease course during pregnancy, however, is unexplored. Here, we provide a first phenotypic and functional characterization of EVs isolated from cultures of term placenta samples of women with MS, differentiating between decidua and trophoblast. In particular, we analyzed the expression profile of 37 surface proteins and tested the functional role of placental EVs on mono-cultures of CD14+ monocytes and co-cultures of CD4+ T and regulatory T (Treg) cells. Results indicated that placental EVs are enriched for surface markers typical of stem/progenitor cells, and that conditioning with EVs from samples of women with MS is associated to a moderate decrease in the expression of proinflammatory cytokines by activated monocytes and in the proliferation rate of activated T cells co-cultured with Tregs. Overall, our findings suggest an immunomodulatory potential of placental EVs from women with MS and set the stage for a promising research field aiming at elucidating their role in MS remission.


Asunto(s)
Vesículas Extracelulares/genética , Inmunidad/genética , Esclerosis Múltiple/genética , Proteoma/genética , Comunicación Celular/genética , Técnicas de Cocultivo , Citocinas/genética , Decidua/inmunología , Decidua/metabolismo , Vesículas Extracelulares/inmunología , Femenino , Humanos , Inmunomodulación/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Placenta/inmunología , Placenta/metabolismo , Embarazo , Linfocitos T Reguladores/inmunología , Trofoblastos/inmunología , Trofoblastos/metabolismo
5.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809384

RESUMEN

Evidence indicates that dysfunctional heterogeneous ribonucleoprotein A1 (hnRNPA1; A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Understanding molecular mechanisms of neurodegeneration in multiple sclerosis may result in novel therapies that attenuate neurodegeneration, thereby improving the lives of MS patients with multiple sclerosis. Using an in vitro, blue light induced, optogenetic protein expression system containing the optogene Cryptochrome 2 and a fluorescent mCherry reporter, we examined the effects of multiple sclerosis-associated somatic A1 mutations (P275S and F281L) in A1 localization, cluster kinetics and stress granule formation in real-time. We show that A1 mutations caused cytoplasmic mislocalization, and significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of clusters. A1 mutations also caused stress granule formation to occur more quickly and frequently in response to blue light stimulation. This study establishes a live cell optogenetics imaging system to probe localization and association characteristics of A1. It also demonstrates that somatic mutations in A1 alter its function and promote stress granule formation, which supports the hypothesis that A1 dysfunction may exacerbate neurodegeneration in multiple sclerosis.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Ribonucleoproteína Nuclear Heterogénea A1/genética , Esclerosis Múltiple/genética , Degeneración Nerviosa/genética , Esclerosis Amiotrófica Lateral/patología , Citoplasma/genética , Citoplasma/metabolismo , Humanos , Esclerosis Múltiple/patología , Mutación/genética
6.
Neurosciences (Riyadh) ; 26(2): 120-127, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33814364

RESUMEN

OBJECTIVES: This review systematically identifies posterior visual pathway lesions and MRI burden in people with multiple sclerosis (MS). METHODS: The articles were searched through Web of Science, Medline, and Embase databases on January 2020, for English language articles from 2000 to 2019. RESULTS: This review presents summary measures if related to MRI assessment to an overall measure of MS and visual pathway lesions. A total of 44 articles fulfilled all inclusion criteria, covering the period 2000-2019. Different atypical outcomes reveal a low risk for subsequent clinically predefined MS development, specifically in the presence of normal brain MRI. Several impairments related to quality of life have been identified as a result of the effect of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer. CONCLUSION: The afferent visual system in MS offers unique accessibility and structure-related functions with further understanding offered by electrophysiology, considering vision as a useful framework for examining new multiple sclerosis therapies.


Asunto(s)
Esclerosis Múltiple/patología , Vías Visuales/patología , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagen , Vías Visuales/diagnóstico por imagen
7.
Science ; 372(6540)2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33888612

RESUMEN

Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.


Asunto(s)
Astrocitos/fisiología , Comunicación Celular , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Microglía/fisiología , Esclerosis Múltiple/fisiopatología , Análisis de la Célula Individual , Animales , Antígenos CD/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Sistema Nervioso Central/fisiopatología , Encefalomielitis Autoinmune Experimental/patología , Efrina-B3/metabolismo , Herpesvirus Suido 1/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Esclerosis Múltiple/patología , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/metabolismo , RNA-Seq , Especies Reactivas de Oxígeno/metabolismo , Receptor EphB3/antagonistas & inhibidores , Receptor EphB3/metabolismo , Receptores de Superficie Celular/metabolismo , Semaforinas/metabolismo , Transducción de Señal , Linfocitos T/fisiología , Serina-Treonina Quinasas TOR/metabolismo
8.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810144

RESUMEN

Multiple sclerosis (MS) has been considered to specifically affect the central nervous system (CNS) for a long time. As autonomic dysfunction including dysphagia can occur as accompanying phenomena in patients, the enteric nervous system has been attracting increasing attention over the past years. The aim of this study was to identify glial and myelin markers as potential target structures for autoimmune processes in the esophagus. RT-PCR analysis revealed glial fibrillary acidic protein (GFAP), proteolipid protein (PLP), and myelin basic protein (MBP) expression, but an absence of myelin oligodendrocyte glycoprotein (MOG) in the murine esophagus. Selected immunohistochemistry for GFAP, PLP, and MBP including transgenic mice with cell-type specific expression of PLP and GFAP supported these results by detection of (1) GFAP, PLP, and MBP in Schwann cells in skeletal muscle and esophagus; (2) GFAP, PLP, but no MBP in perisynaptic Schwann cells of skeletal and esophageal motor endplates; (3) GFAP and PLP, but no MBP in glial cells surrounding esophageal myenteric neurons; and (4) PLP, but no GFAP and MBP in enteric glial cells forming a network in the esophagus. Our results pave the way for further investigations regarding the involvement of esophageal glial cells in the pathogenesis of dysphagia in MS.


Asunto(s)
Biomarcadores , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Esófago/metabolismo , Expresión Génica , Neuroglía/inmunología , Neuroglía/metabolismo , Animales , Sistema Nervioso Central/patología , Femenino , Técnica del Anticuerpo Fluorescente , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Transgénicos , Esclerosis Múltiple/etiología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo
9.
Molecules ; 26(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670164

RESUMEN

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1ß and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1ß and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.


Asunto(s)
Inflamasomas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedades Neurodegenerativas/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Transducción de Señal/genética
10.
Sci Rep ; 11(1): 5402, 2021 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-33686135

RESUMEN

Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.


Asunto(s)
Sistema Nervioso Central/patología , Esclerosis Múltiple/inmunología , Linfocitos T/inmunología , Taurina/análogos & derivados , Animales , Presentación de Antígeno/efectos de los fármacos , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Proliferación Celular/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Ratones Endogámicos C57BL , Esclerosis Múltiple/patología , Proteína Proteolipídica de la Mielina/inmunología , Fragmentos de Péptidos/inmunología , Recurrencia , Bazo/patología , Linfocitos T/efectos de los fármacos , Taurina/farmacología , Ácido gamma-Aminobutírico/farmacología
11.
J Vis Exp ; (168)2021 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-33720130

RESUMEN

Multiple sclerosis (MS) is a neuroinflammatory disease with expanding axonal and neuronal degeneration and demyelination in the central nervous system, leading to motor dysfunctions, psychical disability, and cognitive impairment during MS progression. Positron emission tomography (PET) is an imaging technique able to quantify in vivo cellular and molecular alterations. Radiotracers with affinity to intact myelin can be used for in vivo imaging of myelin content changes over time. It is possible to detect either an increase or decrease in myelin content, what means this imaging technique can detect demyelination and remyelination processes of the central nervous system. In this protocol we demonstrate how to use PET imaging to detect myelin changes in the lysolecithin rat model, which is a model of focal demyelination lesion (induced by stereotactic injection) (i.e., a model of multiple sclerosis disease). 11C-PIB PET imaging was performed at baseline, and 1 week and 4 weeks after stereotaxic injection of lysolecithin 1% in the right striatum (4 µL) and corpus callosum (3 µL) of the rat brain, allowing quantification of focal demyelination (injection site after 1 week) and the remyelination process (injection site at 4 weeks). Myelin PET imaging is an interesting tool for monitoring in vivo changes in myelin content which could be useful for monitoring demyelinating disease progression and therapeutic response.


Asunto(s)
Esclerosis Múltiple/diagnóstico por imagen , Vaina de Mielina/patología , Tomografía de Emisión de Positrones , Compuestos de Anilina/química , Animales , Modelos Animales de Enfermedad , Procesamiento de Imagen Asistido por Computador , Lisofosfatidilcolinas , Imagen por Resonancia Magnética , Ratones Endogámicos C57BL , Esclerosis Múltiple/patología , Ratas , Técnicas Estereotáxicas , Tiazoles/química
12.
Neurology ; 96(14): e1865-e1875, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33737372

RESUMEN

OBJECTIVES: To explore in vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with multiple sclerosis (MS) using [18F]-DPA714 PET and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening. METHODS: Thirty-seven patients with MS and 19 healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3-mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening. RESULTS: The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p = 6.10e-6) and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p = 0.001). This gradient was found in both periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (r s = -0.65, p = 1.0e-3). Compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p = 0.025). CONCLUSIONS: Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and is associated with microstructural damage and disability worsening. This could result from the diffusion of proinflammatory CSF-derived factors into surrounding tissues.


Asunto(s)
Corteza Cerebral/inmunología , Corteza Cerebral/patología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Sustancia Blanca/inmunología , Sustancia Blanca/patología , Adulto , Ventrículos Cerebrales/inmunología , Ventrículos Cerebrales/patología , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones
13.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670394

RESUMEN

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global challenge. Currently, there is some information on the consequences of COVID-19 infection in multiple sclerosis (MS) patients, as it is a newly discovered coronavirus, but its far-reaching effects on participation in neurodegenerative diseases seem to be significant. Recent cases reports showed that SARS-CoV-2 may be responsible for initiating the demyelination process in people who previously had no symptoms associated with any nervous system disorders. It is presently known that infection of SARS-CoV-2 evokes cytokine storm syndrome, which may be one of the factors leading to the acute cerebrovascular disease. One of the substantial problems is the coexistence of cerebrovascular disease and MS in an individual's life span. Epidemiological studies showed an enhanced risk of death rate from vascular disabilities in MS patients of approximately 30%. It has been demonstrated that patients with severe SARS-CoV-2 infection usually show increased levels of D-dimer, fibrinogen, C-reactive protein (CRP), and overactivation of blood platelets, which are essential elements of prothrombotic events. In this review, the latest knowledge gathered during an ongoing pandemic of SARS-CoV-2 infection on the neurodegeneration processes in MS is discussed.


Asunto(s)
/complicaciones , Esclerosis Múltiple/complicaciones , Enfermedades Neurodegenerativas/etiología , Animales , /virología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/virología , Humanos , Esclerosis Múltiple/patología , Esclerosis Múltiple/virología , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/virología , Trombosis/etiología , Trombosis/patología
14.
J Vis Exp ; (168)2021 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-33682856

RESUMEN

The overall goal of this article is to demonstrate a state-of-the-art ultrahigh field (UHF) magnetic resonance (MR) protocol of the brain at 7.0 Tesla in multiple sclerosis (MS) patients. MS is a chronic inflammatory, demyelinating, neurodegenerative disease that is characterized by white and gray matter lesions. Detection of spatially and temporally disseminated T2-hyperintense lesions by the use of MRI at 1.5 T and 3 T represents a crucial diagnostic tool in clinical practice to establish accurate diagnosis of MS based on the current version of the 2017 McDonald criteria. However, the differentiation of MS lesions from brain white matter lesions of other origins can sometimes be challenging due to their resembling morphology at lower magnetic field strengths (typically 3 T). Ultrahigh field MR (UHF-MR) benefits from increased signal-to-noise ratio and enhanced spatial resolution, both key to superior imaging for more accurate and definitive diagnoses of subtle lesions. Hence, MRI at 7.0 T has shown encouraging results to overcome the challenges of MS differential diagnosis by providing MS-specific neuroimaging markers (e.g., central vein sign, hypointense rim structures and differentiation of MS grey matter lesions). These markers and others can be identified by other MR contrasts other than T1 and T2 (T2*, phase, diffusion) and substantially improve the differentiation of MS lesions from those occurring in other neuroinflammatory conditions such as neuromyelitis optica and Susac syndrome. In this article, we describe our current technical approach to study cerebral white and grey matter lesions in MS patients at 7.0 T using different MR acquisition methods. The up-to-date protocol includes the preparation of the MR setup including the radio-frequency coils customized for UHF-MR, standardized screening, safety and interview procedures with MS patients, patient positioning in the MR scanner and acquisition of dedicated brain scans tailored for examining MS.


Asunto(s)
Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Humanos , Procesamiento de Imagen Asistido por Computador , Esclerosis Múltiple/patología , Neuroimagen , Programas Informáticos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología
15.
J Rehabil Med ; 53(4): jrm00178, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33739437

RESUMEN

BACKGROUND: There is insufficient knowledge about how aerobic exercise impacts the disease process of multiple sclerosis, which is characterized by accumulation of white matter lesions and accelerated brain atrophy. OBJECTIVE: To examine the effect of aerobic exercise on neuroinflammation and neurodegeneration by magnetic resonance imaging and clinical measures of disease activity and progression in persons with multiple sclerosis. PATIENTS AND METHODS: An exploratory 12-week randomized control trial including an intervention group (n = 14, 12 weeks of aerobic exercise twice weekly) and a control group (n = 14, continuation of usual lifestyle). Primary outcomes were magnetic resonance imaging measures (lesion load, brain structure volume change), while secondary outcomes included disability measures, blood cytokine levels, cognitive tests and patient-reported outcomes. RESULTS: The effects of aerobic exercise on whole brain and grey matter atrophy were minor. Surprisingly, the observed effect on volume (atrophy) in selected brain substructures was heterogeneous. Putaminal and posterior cingulate volumes decreased, parahippocampal gyrus volume increased, thalamus and amygdala volume remained the same, and active lesion load and count decreased. However, apart from weak improvements in walking speed and brain-derived neurotrophic factor levels, there was no effect of aerobic exercise on other clinical, cognitive or patient-reported outcomes. CONCLUSION: These results suggest that aerobic exercise in persons with multiple sclerosis has a positive effect on the volume of some of the substructures of the brain, possibly indicating a slowing of the neurodegenerative process in these regions, but a negative impact on the volume of some other substructures, with unclear implications. Further research is needed to determine whether the slight decrease in active lesion volume and count implies an anti-inflammatory effect of aerobic exercise, and the exact significance of the heterogeneous results of volumetric assessments.


Asunto(s)
Ejercicio Físico/fisiología , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/terapia , Adulto , Femenino , Humanos , Estudios Longitudinales , Masculino , Esclerosis Múltiple/patología
16.
Life Sci ; 276: 119395, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33781828

RESUMEN

AIMS: STAT3 signaling is critical for Th17 development that plays an important role in multiple sclerosis pathogenesis. To evaluate the anti-inflammatory and regulatory T cells effects of JAK1/2 and STAT3 inhibition, we assessed the JAK 1/2 inhibitor ruxolitinib effects on Th17 cell/Tregs balance. MAIN METHODS: Ruxolitinib was administered to experimental autoimmune encephalomyelitis (EAE) mice via oral gavage, and its effects were assessed. The expression of pro-inflammatory and anti-inflammatory cytokines, including IL-17A and IL-10, were analyzed by real-time PCR. The frequency of Th17 cells and Tregs were evaluated by flow cytometry. KEY FINDING: Ruxolitinib ameliorated the EAE severity and decreased the proportion of Th17 cells and inflammatory markers levels. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine were increased in ruxolitinib-treated mice. Furthermore, ruxolitinib markedly decreased the expression of Th17 related transcription factor, RORÉ£t, whereas FOXP3 expression associated with Treg differentiation was increased. SIGNIFICANCE: Our results show that ruxolitinib may be a promising therapeutic strategy for multiple sclerosis.


Asunto(s)
Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Pirazoles/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Transducción de Señal , Linfocitos T Reguladores/inmunología , Células Th17/inmunología
17.
Nat Neurosci ; 24(4): 489-503, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33603230

RESUMEN

Neurodegeneration occurring in multiple sclerosis (MS) contributes to the progression of disability. It is therefore important to identify and neutralize the mechanisms that promote neurodegeneration in MS. Here, we report that oxidized phosphatidylcholines (OxPCs) found in MS lesions, previously identified as end-product markers of oxidative stress, are potent drivers of neurodegeneration. Cultured neurons and oligodendrocytes were killed by OxPCs, and this was ameliorated by microglia. After OxPC injection, mouse spinal cords developed focal demyelinating lesions with prominent axonal loss. The depletion of microglia that accumulated in OxPC lesions exacerbated neurodegeneration. Single-cell RNA sequencing of lesioned spinal cords identified unique subsets of TREM2high mouse microglia responding to OxPC deposition. TREM2 was detected in human MS lesions, and TREM2-/- mice exhibited worsened OxPC lesions. These results identify OxPCs as potent neurotoxins and suggest that enhancing microglia-mediated OxPC clearance via TREM2 could help prevent neurodegeneration in MS.


Asunto(s)
Glicoproteínas de Membrana/metabolismo , Microglía , Esclerosis Múltiple , Degeneración Nerviosa , Fosfatidilcolinas/toxicidad , Receptores Inmunológicos/metabolismo , Animales , Humanos , Ratones , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuronas/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Oxidación-Reducción , Fosfatidilcolinas/metabolismo
18.
Arch Virol ; 166(4): 1015-1033, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33582855

RESUMEN

Multiple sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous system. Although the etiology of MS is unknown, genetics and environmental factors, such as infections, play a role. Viral infections of mice have been used as model systems to study this demyelinating disease of humans. Three viruses that have long been studied in this capacity are Theiler's murine encephalomyelitis virus, mouse hepatitis virus, and Semliki Forest virus. This review describes the viruses themselves, the infection process, the disease caused by infection and its accompanying pathology, and the model systems and their usefulness in studying MS.


Asunto(s)
Modelos Animales de Enfermedad , Esclerosis Múltiple/patología , Esclerosis Múltiple/virología , Infecciones por Virus ARN/patología , Infecciones por Virus ARN/virología , Animales , Sistema Nervioso Central/patología , Sistema Nervioso Central/fisiología , Sistema Nervioso Central/virología , Humanos , Ratones , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/fisiopatología , Virus de la Hepatitis Murina/patogenicidad , Virus de la Hepatitis Murina/fisiología , Infecciones por Virus ARN/inmunología , Infecciones por Virus ARN/fisiopatología , Virus de los Bosques Semliki/patogenicidad , Virus de los Bosques Semliki/fisiología , Theilovirus/patogenicidad , Theilovirus/fisiología
19.
Mutat Res ; 861-862: 503278, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33551096

RESUMEN

Multiple sclerosis (MS), a disease in which the immune system attacks nerve cells, has been associated with both genetic and environmental risk factors. We observed increased micronucleus (MN) formation in SJL/J mouse experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Most of these MN were due to chromosomal loss. Increased activation of MAP kinases, which leads to disruption of the mitotic spindle and improper segregation of chromosomes, is associated with MS. MAP kinase inhibitors, such as PD98059, may therefore be beneficial for MS. In the EAE model, PD98059 treatment reduced adverse effects, including MN formation, lipid peroxidation, and GSH oxidation. Interventions that mitigate chromosomal instability may have therapeutic value in MS.


Asunto(s)
Inestabilidad Cromosómica/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Flavonoides/farmacología , Proteínas Quinasas Activadas por Mitógenos/química , Esclerosis Múltiple/tratamiento farmacológico , Animales , Encefalomielitis Autoinmune Experimental/complicaciones , Encefalomielitis Autoinmune Experimental/patología , Femenino , Ratones , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/patología
20.
Lancet Neurol ; 20(2): 136-149, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33484648

RESUMEN

The field of acquired CNS neuroimmune demyelination in children is transforming. Progress in assay development, refinement of diagnostic criteria, increased biological insights provided by advanced neuroimaging techniques, and high-level evidence for the therapeutic efficacy of biological agents are redefining diagnosis and care. Three distinct neuroimmune conditions-multiple sclerosis, myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD)-can now be distinguished, with evidence from humans and animal models supporting distinct pathobiological disease mechanisms. The development of highly effective therapies for adult-onset multiple sclerosis and AQP4-NMOSD that suppress relapse rate by more than 90% has motivated advocacy for trials in children. However, doing clinical trials is challenging because of the rarity of these conditions in the paediatric age group, necessitating new approaches to trial design, including age-based trajectory modelling based on phase 3 studies in adults. Despite these limitations, the future for children and adolescents living with multiple sclerosis, MOGAD, or AQP4-NMOSD is far brighter than in years past, and will be brighter still if successful therapies to promote remyelination, enhance neuroprotection, and remediate cognitive deficits can be further accelerated.


Asunto(s)
Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/patología , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Adolescente , Niño , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/terapia , Humanos , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/terapia , Neuroimagen , Adulto Joven
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