Areas Of Demyelination Research Articles

Acetyl-11-keto-beta-boswellic Acid (AKBA) Ameliorates Histopathological and Oxidative Stress Brain Disorders in the Experimental Model of Cuprizone-induced Demyelination

Background: Multiple sclerosis is an inflammatory autoimmune disease that destroys the myelin sheath (demyelination) and neurons of the central nervous system (CNS), with several factors contributing to its development. Objectives: This study investigated the impact of administering acetyl 11-keto-beta boswellic acid (AKBA) in an animal model of cuprizone-induced demyelination. Methods: Thirty-two C57BL/6 female mice (WT; 20 - 25 g, 8 - 10 weeks old) were randomly divided into four groups: (1) Control (CO), (2) Cuprizone-treated (CPZ, 0.3%), (3) AKBA + CPZ (50 mg/kg, pre-treatment), and (4) CPZ + AKBA (50 mg/kg, post-treatment). At the end of the study, the weight and movement balance of the animals were assessed using the rotarod test. After sampling the brain, the extent of the demyelination area in the corpus callosum was measured with Luxol Fast Blue staining, the number of oligodendrocyte cells was determined by immunohistochemistry, and the levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) as oxidative stress factors in the brain tissue were measured. Results: The use of acetyl-11-keto-beta boswellic acid in the cuprizone-induced demyelination model prevented weight loss, increased animal resistance in the rotarod test, and reduced the demyelination rate in the corpus callosum. Additionally, AKBA elevated the number of oligodendrocytes and total antioxidant capacity levels while reducing malondialdehyde levels in brain tissue. Pretreatment with AKBA exhibited a more significant effect. Conclusions: This study showed that acetyl-11-keto-beta boswellic acid, an important active substance of the frankincense plant, likely protects the nervous system and neurons in the cuprizone-induced demyelination model by preventing the decrease in the number of oligodendrocytes, reducing oxidative stress, and preventing the destruction of myelin.

Effects of aerobic exercise on demyelination and brain morphology in the cuprizone rat model of multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that led to brain atrophy. The purpose of this study was to investigate the effects of pre-and post-conditioning with exercise on demyelination and brain morphology. Thirty male rats were randomly divided into five groups (n = 6 per group), consisting of a healthy control group (Control), an MS group, and three exercise groups: the group that performed the exercise protocol (running on a treadmill 5 days/week for 6 weeks) before the MS induction (EX + MS), the group that performed the exercise protocol during the MS induction (MS + EX), and the group that performed the exercise protocol before and during the MS induction (EX + MS + EX). The expression of Myelin basic protein (MBP), and demyelination in the corpus callosum and the volume, weight, length, width, and height of the brain were measured. The EX + MS + EX showed a significant increase in the expression of MBP compared to other MS groups (**p < 0.01) as well as a significant decrease in the area of demyelination of the corpus callosum compared to MS and MS + EX groups (**p < 0.01). However, there were no significant differences between the MS group and exercised groups for brain morphology. The exercise showed neuroprotective effects, as evidenced by decreased areas of demyelination and improved MBP expression.

Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination.

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

Melatonin synergistically potentiates the effect of methylprednisolone on reducing neuroinflammation in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of unknown etiology characterized by infiltration of encephalitogenic cells in the central nervous system (CNS) resulting in the presence of multifocal areas of demyelination leading to neurodegeneration. The infiltrated immune cells population is composed mainly of effector CD4+ and CD8+ T lymphocytes, B cells, macrophages, and dendritic cells that secrete pro-inflammatory factors that eventually damage myelin leading to axonal damage. The most common clinical form of MS is relapsing-remitting (RR), characterized by neuroinflammatory episodes followed by partial or total recovery of neurological deficits. The first-line treatment for RRMS relapses is a high dose of glucocorticoids, especially methylprednisolone, for three to five consecutive days. Several studies have reported the beneficial effects of melatonin in the context of neuroinflammation associated with MS or experimental autoimmune encephalomyelitis (EAE), the preclinical model for MS. Therefore, the objective of this study was to evaluate the effect of the combined treatment of melatonin and methylprednisolone on the neuroinflammatory response associated with the EAE development. This study shows for the first time the protective synergistic effect of co-treatment with melatonin and methylprednisolone on reducing the severity of EAE by decreasing CD4 lymphocytes, B cells, macrophages and dendritic cells in the CNS, as well as modulating the population of infiltrated T and B cells toward regulatory phenotypes to the detriment of pro-inflammatory effector functions. In addition to the potentiation of the protective role of methylprednisolone, treatment with melatonin from the clinical onset of EAE improves the natural course of the EAE and the response to a subsequent treatment with methylprednisolone in a later relapse of the disease, pointing melatonin as potential therapeutic tool in combination with methylprednisolone for the treatment of relapses in MS.

Olig2-enriched exosomes: A novel therapeutic approach for cuprizone-induced demyelination

The research aims to study the therapeutic impact of HEK293-XPack-Olig2 cell-derived exosomes on remyelination of the corpus callosum in a cuprizone-induced demyelinating disease model. A lentiviral vector expressing Olig2 was constructed using XPack technology. The highly abundant Olig2 exosomes (ExoOs) were isolated by centrifugation for subsequent experiments. Western blot, nanoparticle tracking analysis (NTA), and electron microscopy showed no significant difference in particle size and morphology between Exos and ExoOs, and a high level of Olig2 expression could be detected in ExoOs, indicating that exosome modification by XPack technology was successful. The Black Gold/Fluromyelin staining analysis showed that the ExoOs group significantly reduced the demyelination area in the corpus callosum compared to the PBS and Exos groups. Additionally, the PDGFRα/APC staining of the demyelinating region revealed an increase in APC+ oligodendrocytes and a decrease in PDGFRα+ oligodendrocyte progenitor cells (OPCs) in the ExoOs group. Furthermore, there was evident myelin regeneration in the demyelinated areas after ExoOs treatment, with better g-ratio and a higher number of intact myelin compared to the other treatment groups. The level of Sox10 expression in the brain tissue of the ExoOs group were higher compared to those of the PBS and Exos groups. The demyelination process can be significantly slowed down by the XPack-modified exosomes, the differentiation of OPCs promoted, and myelin regeneration accelerated under pathological conditions. This process is presumed to be achieved by changing the expression level of intracellular differentiation-related genes after exosomes transport Olig2 enriched into oligodendrocyte progenitors.

L’anisocorie intermittente comme signe révélateur de la sclérose en plaques récurrente-rémittente

A 36-year-old male presented for an examination reporting intermittent anisocoria of one week duration. Over a period of one-month, ocular findings consisted of intermittent and variable anisocoria, diplopia, and torsional nystagmus. A diagnosis of relapsing-remitting multiple sclerosis (MS) was made using the McDonald criteria based on brainstem syndrome, optic neuropathy, transverse myelitis symptoms, multifocal areas of demyelination in the spinal cord on MRI, and the absence of MS mimickers in lab work. In this case report, eye care providers are alerted to the possibility of intermittent anisocoria as a presenting sign of relapsing-remitting multiple sclerosis.

ASK1 activation in glial cells in post-mortem multiple sclerosis tissue.

Multiple sclerosis (MS), the leading cause of disability in young adults, is an inflammatory disease of the central nervous system characterized by localized areas of demyelination. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been shown to be implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Interestingly, ASK1 signaling regulates glial cell interactions and drives neuroinflammation in EAE mice. To further investigate its clinical significance, in the present study, we examined the activation of ASK1 in the post-mortem brain of MS patients. ASK1 activation was found in active lesions of the corpus callosum in both microglia/macrophages and astrocytes. Moreover, ASK1 activation in astrocytes was higher than that in microglia/macrophages, which was in line with our findings in EAE mice. Our results suggest an important role of ASK1 in glial cells, indicating that ASK1 might be a good therapeutic target for MS.

Lactate Dehydrogenase-Elevating Virus Infection Inhibits MOG Peptide Presentation by CD11b+CD11c+ Dendritic Cells in a Mouse Model of Multiple Sclerosis.

Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) experienced paralysis and lost weight at a greater rate than mice who had previously been infected with LDV. LDV infection decreased the presentation of the MOG peptide by CD11b+CD11c+ dendritic cells (DC) to pathogenic T lymphocytes. When comparing non-infected mice to infected mice, the histopathological examination of the CNS showed more areas of demyelination and CD45+ and CD3+, but not Iba1+ cell infiltration. These results suggest that the protective effect of LDV infection against EAE development is mediated by a suppression of myelin antigen presentation by a specific DC subset to autoreactive T lymphocytes. Such a mechanism might contribute to the general suppressive effect of infections on autoimmune diseases known as the hygiene hypothesis.

Modern ideas about concentric sclerosis Balo: a clinical case

Balo's concentric sclerosis (BCS) is a rare demyelinating disease of the central nervous system, characterized by concentric areas of demyelination alternating with areas of preserved myelin in the form of a pathognomonic pathomorphological substrate of varying degrees of severity in the form of «annual rings on a tree cut». The pathogenesis of BCS is diverse and complex, today there are several theories of its occurrence, among which hypoxic, vascular and closely related genetic, as well as a number of other theories are distinguished. The BCS clinic is variable, represented by both focal neurological manifestations and general cerebral symptoms. The diagnosis is based on the data of magnetic resonance imaging of the brain. The drugs of choice for BCS therapy are glucocorticosteroids (prednisolone or methylprednisolone).

TRAF6 signaling in T cells is crucial for the pathogenicity of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an incurable chronic autoimmune disease affecting the central nervous system (CNS). Although IL-17-producing helper T (Th17) cells are thought to be one of the exacerbating factors in MS, the underlying pathogenic mechanism is incompletely understood. TNF receptor-associated factor 6 (TRAF6) deficient T cells exhibited enhanced Th17 cell differentiation, however, the physiological relevance of TRAF6 in T cells remains unknown. Here, we induced experimental autoimmune encephalomyelitis (EAE) in T cell-specific TRAF6 deficient (TRAF6ΔT) mice to investigate the role of TRAF6 in T cells during the course of MS using an EAE model. Although Th17 cell differentiation was enhanced in TRAF6ΔT mice, mutant mice were resistant to EAE. In contrast, TRAF6 loss did not affect regulatory T-cell differentiation. Consistent with the severity of EAE, a small number of infiltrating T cells and a small area of demyelination were observed in the CNS of TRAF6ΔT mice. Moreover, myelin oligodendrocyte glycoprotein-induced IL-17 production in TRAF6-deficient T cells was significantly suppressed. We further confirmed lower levels of CD69 and granulocyte-macrophage colony-stimulating factor in Th17 cells of TRAF6ΔT mice than in wild-type mice. In contrast, the expression of IL-10 and cytotoxic T-lymphocyte-associated protein 4 in T cells was significantly elevated in the absence of TRAF6 because of enhanced T-cell receptor signaling. Collectively, TRAF6 signaling in T cells contributes to the pathogenesis of EAE by regulating the pathogenicity and autoantigen reactivity of Th17 cells.

Associations between cortical lesions, optic nerve damage, and disability at the onset of multiple sclerosis: insights into neurodegenerative processes.

BackgroundMultiple sclerosis cortical lesions are areas of demyelination and neuroaxonal loss. Retinal layer thickness, measured with optical coherence tomography (OCT), is an emerging biomarker of neuroaxonal loss. Studies have reported correlations between cortical lesions and retinal layer thinning in established multiple sclerosis, suggesting a shared pathophysiological process. Here, we assessed the correlation between cortical lesions and OCT metrics at the onset of multiple sclerosis, examining, for the first time, associations with physical or cognitive disability. ObjectiveTo examine the relationship between cortical lesions, optic nerve and retinal layer thicknesses, and physical and cognitive disability at the first demyelinating event. MethodsThirty-nine patients and 22 controls underwent 3T-MRI, optical coherence tomography, and clinical tests. We identified cortical lesions on phase-sensitive inversion recovery sequences, including occipital cortex lesions. We measured the estimated total intracranial volume and the white matter lesion volume. OCT metrics included peripapillary retinal nerve fibre layer (pRNFL), ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses. ResultsHigher total cortical and leukocortical lesion volumes correlated with thinner pRNFL (B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01; B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01, respectively). Leukocortical lesion number correlated with colour vision deficits (B = 0.58, 95 %CI 0.039 to 1,11, p = 0.036). Thinner GCIPL correlated with a higher Expanded Disability Status Scale (B = -0.06, 95 % CI -1.1 to -0.008, p = 0.026). MS diagnosis (n = 18) correlated with higher cortical and leukocortical lesion numbers (p = 0.004 and p = 0.003), thinner GCIPL (p = 0.029) and INL (p = 0.041). ConclusionThe association between cortical lesions and axonal damage in the optic nerve reinforces the role of neurodegenerative processes in MS pathogenesis at onset.

Improving cognition in people with multiple sclerosis: study protocol for a multiarm, randomised, blinded trial of multidomain cognitive rehabilitation using a video-serious game (E-SEP cognition)

IntroductionMultiple sclerosis (MS) is a prevalent neurological disease characterised by disseminated areas of demyelination and atrophy within the central nervous system, inducing cognitive disorders in 45%–65% of persons with MS...

Inhibition of SUMOylation promotes remyelination and reduces IL-17 mediated autoimmune inflammation: Novel approach toward treatment of inflammatory CNS demyelinating disease

Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. In the CNS, expression of myelin genes is regulated by state of SUMOylation of their respective transcription factors. In the immune system, deSUMOylation activates innate immune responses and promotes anti-viral immunity. However, the role played by SUMO in an adaptive immune response and in the development of T cell mediated autoimmune disease has not been previously described.TAK981 is a synthetic small molecule which by forming adducts with SUMO proteins prevents SUMOylation. We examined the expression of myelin genes and their transcription factors following culture with TAK981 in Oligodendrocyte Precursor Cells (OPC). We found that myelin basic protein (MBP), a key myelin protein, is upregulated in OPC in the presence of TAK981. We also found increased expression of transcription factors Sox10 and Myrf, which engage in the expression of MBP. In the Cuprizone model of demyelination/remyelination, animals which were treated with TAK981 showed increased remyelination in areas of demyelination and an increase in the number of maturing oligodendrocytes compared to vehicle treated controls. In in vitro cultures of lymphocytes, TAK981 reduced the expression of TH17 in T cells in mice immunized with MOGp35–55. Following in vivo treatment with TAK981, there was a significant reduction in the clinical and pathological severity in mice immunized to develop experimental allergic encephalitis (EAE).The dual effects of deSUMOylation on remyelination and in regulating an autoimmune adaptive response offers a novel approach to the management of human inflammatory demyelinating diseases such as multiple sclerosis.

Expression of functionally distinct ecto-5'-nucleotidase/CD73 glycovariants in reactive astrocytes in experimental autoimmune encephalomyelitis and neuroinflammatory conditions in vitro.

Ecto-5'-nucleotidase/CD73 (eN/CD73) is a membrane-bound enzyme involved in extracellular production of adenosine and a cell adhesion molecule involved in cell-cell interactions. In neuroinflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), reactive astrocytes occupying active demyelination areas significantly upregulate eN/CD73 and express additional eN/CD73 variants. The present study investigated whether the different eN/CD73 variants represent distinct glycoforms and the functional consequences of their expression in neuroinflammatory states. The study was performed in animals at different stages of EAE and in primary astrocyte cultures treated with a range of inflammatory cytokines. Upregulation at the mRNA, protein, and functional levels, as well as the appearance of multiple eN/CD73 glycovariants were detected in the inflamed spinal cord tissue. At the peak of the disease, eN/CD73 exhibited higher AMP turnover and lower enzyme-substrate affinity than the control group, which was attributed to altered glycosylation under neuroinflammatory conditions. A subsequent in vitro study showed that primary astrocytes upregulated eN/CD73 and expressed the multiple glycovariants upon stimulation with TNFα, IL-1β, IL-6, and ATP, with the effect occurring at least in part via induction of JAK/STAT3 signaling. Experimental removal of glycan moieties from membrane glycoproteins by PNGaseF decreased eN/CD73 activity but had no effect on the enzyme's involvement in astrocyte migration. Our results suggest that neuroinflammatory states are associated with the appearance of functionally distinct eN/CD73 glycovariants, which may play a role in the development of the reactive astrocyte phenotype.

Autopsy evidence of central and peripheral demyelination in a case of Guillain-Barré syndrome/ Bickerstaff brainstem encephalitis overlap syndrome

We report a case of a 59-year-old male who had acute, severe, rapidly progressive ascending weakness, which progressed to difficulty of breathing in a span of twelve hours. Neurophysiologic studies showed acute denervation compatible with acute motor axonal neuropathy. He was started on intravenous immunoglobulin therapy on the first day of hospitalization and completed five days of treatment but still developed decrease in sensorium and bilateral ophthalmoplegia. Imaging studies of the brain and cervical spinal cord showed findings that are non-contributory to the clinical presentation, leading to the consideration of Bickerstaff’s brainstem encephalitis. Pulse therapy with high dose methylprednisolone for five days was given however, despite maximal treatment, he expired on the 12th day of illness. Post-mortem immunohistochemical studies of the pons and sural nerve showed areas of inflammation and demyelination in both areas, suggesting combined central and peripheral demyelination in a single patient. Literature review shows that our patient presents with atypical clinical and diagnostic features, different from Bickerstaff’s brainstem encephalitis and combined central and peripheral demyelination, suggesting another disease entity presenting as acute fulminant neuropathy.

"Combo" Multi-Target Pharmacological Therapy and New Formulations to Reduce Inflammation and Improve Endogenous Remyelination in Traumatic Spinal Cord Injury.

Spinal cord injury (SCI) is characterized by a cascade of events that lead to sensory and motor disabilities. To date, this condition is irreversible, and no cure exists. To improve myelin repair and limit secondary degeneration, we developed a multitherapy based on nanomedicines (NMeds) loaded with the promyelinating agent triiodothyronine (T3), used in combination with systemic ibuprofen and mouse nerve growth factor (mNGF). Poly-L-lactic-co-glycolic acid (PLGA) NMeds were optimized and loaded with T3 to promote sustained release. In vitro experiments confirmed the efficacy of T3-NMeds to differentiate oligodendrocyte precursor cells. In vivo rat experiments were performed in contusion SCI to explore the NMed biodistribution and efficacy of combo drugs at short- and long-term post-lesion. A strong anti-inflammatory effect was observed in the short term with a reduction of type M1 microglia and glutamate levels, but with a subsequent increase of TREM2. In the long term, an improvement of myelination in NG2-IR, an increase in MBP content, and a reduction of the demyelination area were observed. These data demonstrated that NMeds can successfully be used to obtain more controlled local drug delivery and that this multiple treatment could be effective in improving the outcome of SCIs.

Myelin Water Fraction of Slowly Evolving Lesions is Associated With Disability in Multiple Sclerosis (P10-3.017)

Myelin Water Fraction of Slowly Evolving Lesions is Associated With Disability in Multiple Sclerosis (P10-3.017)

Intravenous immunoglobulin preparations attenuate lysolecithin-induced peripheral demyelination in mice and comprise anti-large myelin protein zero antibody.

Intravenous immunoglobulin (IVIg) has been used to treat inflammatory demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, and multifocal motor neuropathy. Despite studies demonstrating the clinical effectiveness of IVIg, the mechanisms underlying its effects remain to be elucidated in detail. Herein, we examined the effects of IVIg on lysolecithin-induced demyelination of the sciatic nerve in a mouse model. Mice -administered with IVIg 1 and 3 days post-injection (dpi) of lysolecithin -exhibited a significantly decreased demyelination area at 7 dpi. Immunoblotting analysis using two different preparations revealed that IVIg reacted with a 36-kDa membrane glycoprotein in the sciatic nerve. Subsequent analyses of peptide absorption identified the protein as a myelin protein in the peripheral nervous system (PNS) known as large myelin protein zero (L-MPZ). Moreover, injected IVIg penetrated the demyelinating lesion, leading to deposition on L-MPZ in the myelin debris. These results indicate that IVIg may modulate PNS demyelination, possibly by binding to L-MPZ on myelin debris.

Microglia-derived CCL2 has a prime role in neocortex neuroinflammation

BackgroundIn myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), several areas of demyelination are detectable in mouse cerebral cortex, where neuroinflammation events are associated with scarce inflammatory infiltrates and blood–brain barrier (BBB) impairment. In this condition, the administration of mesenchymal stem cells (MSCs) controls neuroinflammation, attenuating astrogliosis and promoting the acquisition of stem cell traits by astrocytes. To contribute to the understanding of the mechanisms involved in the pathogenesis of EAE in gray matter and in the reverting effects of MSC treatment, the neocortex of EAE-affected mice was investigated by analyzing the cellular source(s) of chemokine CCL2, a molecule involved in immune cell recruitment and BBB-microvessel leakage.MethodsThe study was carried out by immunohistochemistry (IHC) and dual RNAscope IHC/in situ hybridization methods, using astrocyte, NG2-glia, macrophage/microglia, and microglia elective markers combined with CCL2.ResultsThe results showed that in EAE-affected mice, hypertrophic microglia are the primary source of CCL2, surround the cortex neurons and the damaged BBB microvessels. In EAE-affected mice treated with MSCs, microgliosis appeared diminished very soon (6 h) after treatment, an observation that was long-lasting (tested after 10 days). This was associated with a reduced CCL2 expression and with apparently preserved/restored BBB features. In conclusion, the hallmark of EAE in the mouse neocortex is a condition of microgliosis characterized by high levels of CCL2 expression.ConclusionsThis finding supports relevant pathogenetic and clinical aspects of the human disease, while the demonstrated early control of neuroinflammation and BBB permeability exerted by treatment with MSCs may have important therapeutic implications.