Emergent Management of Central Nervous System Demyelinating Disorders.

OBJECTIVE: This article reviews the various conditions that can present with acute and severe central nervous system demyelination, the broad differential diagnosis of these conditions, the most appropriate diagnostic workup, and the acute treatment regimens to be administered to help achieve the best possible patient outcomes. LATEST DEVELOPMENTS: The discovery of anti-aquaporin 4 (AQP4) antibodies and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in the past two decades has revolutionized our understanding of acute demyelinating disorders, their evaluation, and their management. ESSENTIAL POINTS: Demyelinating disorders comprise a large category of neurologic disorders seen by practicing neurologists. In the majority of cases, patients with these conditions do not require care in an intensive care unit. However, certain disorders may cause severe demyelination that necessitates intensive care unit admission because of numerous simultaneous multifocal lesions, tumefactive lesions, or lesions in certain brain locations that lead to acute severe neurologic dysfunction. Intensive care may be necessary for the management and prevention of complications for patients who have severely altered mental status, rapidly progressive neurologic worsening, elevated intracranial pressure, severe cerebral edema, status epilepticus, or respiratory failure.

Extracellular vesicles containing miR-181a-5p as a novel therapy for experimental autoimmune encephalomyelitis-induced demyelination.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Recent research has revealed that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), containing specific miRNAs, possess immunomodulatory properties and have demonstrated therapeutic potential in the treatment of MS. This study aimed to investigate the role MSC-EVs, containing microRNA-181a-5p (miR-181a-5p) in both experimental autoimmune encephalomyelitis (EAE), an established animal model of MS, and lipopolysaccharide-stimulated BV2 microglia. We evaluated clinical symptoms and inflammatory responses in EAE mice following intrathecal injections of MSC-EVs. MSC-EVs containing miR-181a-5p were co-cultured with microglia to explore their impact on inflammation and cell pyroptosis. We validated the interaction between miR-181a-5p and its downstream regulators and conducted in vivo verification by injecting manipulated EVs containing miR-181a-5p into EAE mice. Our results demonstrated that MSC-EVs, containing miR-181a-5p reduced the clinical symptoms of EAE mice. Furthermore, we observed downregulation of miR-181a-5p in EAE model mice, and its expression was restored after treatment with MSC-EVs, which corresponded to suppressed microglial inflammation and pyroptosis. Additionally, EVs containing miR-181a-5p mitigated spinal cord injury and demyelination in EAE mice. Mechanistically, ubiquitin-specific protease 15 (USP15) exhibited high expression in EAE mice, and miR-181a-5p was specifically targeted and bound to USP15, thereby regulating the RelA/NEK7 axis. In conclusion, MSC-EVs containing miR-181a-5p inhibit microglial inflammation and pyroptosis through the USP15-mediated RelA/NEK7 axis, thus alleviating the clinical symptoms of EAE. These findings present a potential therapeutic approach for the treatment of MS.

Vagus nerve stimulation enhances remyelination and decreases innate neuroinflammation in lysolecithin-induced demyelination.

BACKGROUND: Current treatments for Multiple Sclerosis (MS) poorly address chronic innate neuroinflammation nor do they offer effective remyelination. The vagus nerve has a strong regulatory role in inflammation and Vagus Nerve Stimulation (VNS) has potential to affect both neuroinflammation and remyelination in MS. OBJECTIVE: This study investigated the effects of VNS on demyelination and innate neuroinflammation in a validated MS rodent model. METHODS: Lysolecithin (LPC) was injected in the corpus callosum (CC) of 46 Lewis rats, inducing a demyelinated lesion. 33/46 rats received continuously-cycled VNS (cVNS) or one-minute per day VNS (1minVNS) or sham VNS from 2 days before LPC-injection until perfusion at 3 days post-injection (dpi) (corresponding with a demyelinated lesion with peak inflammation). 13/46 rats received cVNS or sham from 2 days before LPC-injection until perfusion at 11 dpi (corresponding with a partial remyelinated lesion). Immunohistochemistry and proteomics analyses were performed to investigate the extend of demyelination and inflammation. RESULTS: Immunohistochemistry showed that cVNS significantly reduced microglial and astrocytic activation in the lesion and lesion border, and significantly reduced the Olig2+ cell count at 3 dpi. Furthermore, cVNS significantly improved remyelination with 57.4 % versus sham at 11 dpi. Proteomic gene set enrichment analyses showed increased activation of (glutamatergic) synapse pathways in cVNS versus sham, most pronounced at 3 dpi. CONCLUSION: cVNS improved remyelination of an LPC-induced lesion. Possible mechanisms might include modulation of microglia and astrocyte activity, increased (glutamatergic) synapses and enhanced oligodendrocyte clearance after initial injury.

Progressive demyelinating polyneuropathy after hematopoietic cell transplantation in metachromatic leukodystrophy: a case series.

Metachromatic leukodystrophy (MLD) is a neuro-metabolic disorder due to arylsulfatase A deficiency, causing demyelination of the central and peripheral nervous system. Hematopoietic cell transplantation (HCT) can provide a symptomatic and survival benefit for pre-symptomatic and early symptomatic patients by stabilizing CNS disease. This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support. The patients had demyelinating polyneuropathy before HCT, performed at the ages of 2 years in the first two patients and at 14 and 23 years in the other two patients. The myeloablative conditioning regimen consisted of busulfan, fludarabine and, in one case, rituximab, with anti-thymocyte globulin, cyclosporine, steroids, and/or mycophenolate mofetil for GvHD prophylaxis. Polyneuropathy after HCT progressed parallel with tapering immunosuppression and paralleled bouts of infection and graft-versus-host disease (GvHD). Differential diagnoses included MLD progression, neurological GvHD or another (auto)inflammatory cause. Laboratory, electroneurography and pathology investigations were inconclusive. In two patients, treatment with immunomodulatory drugs led to temporary improvement, but not sustained stabilization of polyneuropathy. One patient showed recovery to pre-HCT functioning, except for a Holmes-like tremor, for which a peripheral origin cannot be excluded. One patient showed marginal response to immunosuppressive treatment and died ten months after HCT due to respiratory failure. The extensive diagnostic and therapeutic attempts highlight the challenge of characterizing and treating progressive polyneuropathy in patients with MLD shortly after HCT. We advise to consider repeat electro-neurography and possibly peripheral nerve biopsy in such patients. Nerve conduction blocks, evidence of the presence of T lymphocytes and macrophages in the neuronal and surrounding nerve tissue, and beneficial effects of immunomodulatory drugs may indicate a partially (auto)immune-mediated pathology. Polyneuropathy may cause major residual disease burden after HCT. MLD patients with progressive polyneuropathy could potentially benefit from a more intensified immunomodulatory drug regime following HCT, especially at times of immune activation.

Efficacy and comparison of corticosteroids only and corticosteroids with plasmapheresis or intravenous immunoglobulin for the treatment of optic neuritis in demyelinating disease: A systematic review and network meta-analysis.

PURPOSE: To compare the efficacy of treatment of optic neuritis (ON) with corticosteroids (CTC) alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). DESIGN: After an episode of ON, although visual recovery is usually good, some patients may have significant visual sequelae. While the efficacy of first-line CTC is now indisputable, there is no consensus on the nature of second-line treatment. To date, no systematic review has compared the efficacy of treatment of ON with CTC alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). A meta-analysis is needed to compare the efficacy of PLP and IVIG in steroid-resistant ON. METHODS: This systematic review included all studies comparing at least two of the three treatments for steroid-resistant ON (CTC alone, CTC+PLP, and CTC+IVIG). From all articles published on PubMed between January 2000 and June 2022, two independent ophthalmologists selected studies of interest using the PRISMA method. Methodology, patient characteristics, and outcomes were identified. A network metaanalysis was then performed to compare the efficacy of the three treatments. RESULTS: Six comparative studies were included, representing 209 patients. The percentage of significant visual recovery after CTC alone, CTC+PLP, and CTC+IVIG in the acute treatment of steroid-resistant ON was 30 %, 45 %, and 77 %, respectively. Comparison of CTC+IVIG vs CTC alone, CTC+PLP vs CTC only, and CTC+PLP vs CTC+IVIG yielded odds ratios of 12.81, 2.47, and 0.19 respectively. CONCLUSION: Treatment of steroid-resistant ON with CTC+PLP or CTC+IVIG is more effective than treatment with CTC alone. Although no study has directly compared the two treatments, IVIG may be more effective than PLP.

Engineered PDGFA-ligand-modified exosomes delivery T3 for demyelinating disease targeted therapy.

Demyelination is a proper syndrome in plenty of central nervous system (CNS) diseases, which is the main obstacle to recovery and still lacks an effective treatment. To overcome the limitations of the brain-blood barrier on drug permeability, we modified an exosome secreted by neural stem cells (NSCs), which had transfected with lentivirus armed with platelet-derived growth factors A (PDGFA)-ligand. Through the in vivo and in vitro exosomes targeting test, the migration ability to the lesion areas and OPCs significantly improved after ligand modification. Furthermore, the targeted exosomes loaded with 3,5, 30-L-triiodothyronine (T3) have a critical myelination ability in CNS development, administrated to the cuprizone animal model treatment. The data shows that the novel drug vector loaded with T3 significantly promotes remyelination compared with T3 alone. At the same time, it improved the CNS microenvironment by reducing astrogliosis, inhibiting pro-inflammatory microglia, and alleviating axon damage. This investigation provides a straightforward strategy to produce a targeting exosome and indicates a possible therapeutic manner for demyelinating disease.

Clinical and radiological characteristics and outcomes of patients with recurrent or relapsing tumefactive demyelination.

BACKGROUND: Relapsing or recurrent tumefactive demyelination is rare and has not been studied beyond individual case reports. OBJECTIVE: We examined the clinical course, neuroimaging, cerebrospinal fluid (CSF), treatment and outcomes of patients with recurrent tumefactive demyelinating lesions (TDLs). METHODS: We used PubMed to identify reports of recurrent TDLs and included the details of an additional, unpublished patient. RESULTS: We identified 18 cases (11F, 7 M). The median age at onset of the index TDL was 37 years (range 12-72) and most were solitary lesions 72 % (13/18). CSF-restricted oligoclonal bands (OCBs) were detected in 25 % (4/16). Only one of those tested (n = 13) was positive for AQP4-IgG. A moderate-to-marked treatment response (high dose corticosteroid with or without additional plasmapheresis, IVIg or disease modifying therapies) was evident in 89 % of treated patients. Median EDSS at the median follow-up of 36 months (range 6-144) was 2 (range 1-10). Most remained ambulatory (EDSS < 4 in 13/18), but 1 patient died. CONCLUSION: The median age of patients with relapsing TDLs is similar to that of typical MS, but differences include a lower female:male sex ratio, larger lesions, and a comparative lack of CSF-restricted OCBs. Outcomes vary among this group of patients ranging from minimal disability through to death.

Osmotic demyelination as a complication of hyponatremia correction: a systematic review.

BACKGROUND: Rapid correction of hyponatremia, especially when severe and chronic, can result in osmotic demyelination. The latest guideline for diagnosis and treatment of hyponatremia (2014) recommends a correction limit of 10 mEq/L/day. Our aim was to summarize published cases of osmotic demyelination to assess the adequacy of this recommendation. METHOD: Systematic review of case reports of osmotic demyelination. We included cases confirmed by imaging or pathology exam, in people over 18 years of age, published between 1997 and 2019, in English or Portuguese. RESULTS: We evaluated 96 cases of osmotic demyelination, 58.3% female, with a mean age of 48.2 ± 12.9 years. Median admission serum sodium was 105 mEq/L and > 90% of patients had severe hyponatremia (<120 mEq/L). Reports of gastrointestinal tract disorders (38.5%), alcoholism (31.3%) and use of diuretics (27%) were common. Correction of hyponatremia was performed mainly with isotonic (46.9%) or hypertonic (33.7%) saline solution. Correction of associated hypokalemia occurred in 18.8%. In 66.6% of cases there was correction of natremia above 10 mEq/L on the first day of hospitalization; the rate was not reported in 22.9% and in only 10.4% was it less than 10 mEq/L/day. CONCLUSION: The development of osmotic demyelination was predominant in women under 50 years of age, with severe hyponatremia and rapid correction. In 10.4% of cases, there was demyelination even with correction <10 mEq/L/day. These data reinforce the need for conservative targets for high-risk patients, such as 4-6 mEq/L/day, not exceeding the limit of 8 mEq/L/day.

Pediatric anti-NMDAR encephalitis with demyelination on brain MRI: A single center study.

OBJECTIVE: To explore the clinical characteristics, immunotherapy response, and prognosis of pediatric anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis associated with demyelination on brain magnetic resonance (MRI). METHODS: We retrospectively reviewed the medical records of children diagnosed with anti-NMDAR encephalitis in our hospital between January 2016 and December 2021. All children with evidence of demyelination on brain MRI were included. RESULTS: A total of 183 anti-NMDAR encephalitis children were included; 8.7 % (16/183) of them had demyelination on brain MRI. Nine were positive for myelin oligodendrocyte glycoprotein (MOG)-IgG, while two were positive for both MOG-IgG and glial fibrillary acidic protein (GFAP)-IgG. Four patients had a history of acquired demyelinating syndromes and encephalitis, respectively, while nine (56.3 %) had atypical symptoms of anti-NMDAR encephalitis. All children had supratentorial demyelination on brain MRI; four of them had additional infratentorial lesions. All children received first-line immunotherapy; four were administered repeated first-line immunotherapy and/or rituximab because of poor initial response. During the follow-up, 37.5 % (6/16) of the children relapsed, but all responded well to immunotherapy. There were no significant differences in mRS score before immunotherapy, response to first-line immunotherapy, and long-term prognosis between anti-NMDAR encephalitis children with and without demyelination. However, patients with demyelination were more likely to have a history of acquired demyelinating syndromes or unexplained cortical encephalitis and to relapse. CONCLUSION: Pediatric anti-NMDAR encephalitis can co-occur with demyelination and has a high rate of MOG-IgG positivity. A history of acquired demyelinating syndromes or unexplained cortical encephalitis and atypical symptoms may indicate demyelination in children with anti-NMDAR encephalitis. Pediatric anti-NMDAR encephalitis with demyelination is more likely to relapse and needs a closer follow-up. However, it remains unknown whether more intensive immunotherapy is required in these patients.

Polycaprolactone/graphene oxide/acellular matrix nanofibrous scaffolds with antioxidant and promyelinating features for the treatment of peripheral demyelinating diseases.

Peripheral demyelinating diseases entail damage to axons and Schwann cells in the peripheral nervous system. Because of poor prognosis and lack of a cure, this group of diseases has a global impact. The primary underlying cause of these diseases involves the inability of Schwann cells to remyelinate the damaged insulating myelin around axons, resulting in neuronal death over time. In the past decade, extensive research has been directed in the direction of Schwann cells focusing on their physiological and neuroprotective effects on the neurons in the peripheral nervous system. One cause of dysregulation in the remyelinating function of Schwann cells has been associated with oxidative stress. Tissue-engineered biodegradable scaffolds that can stimulate remyelination response in Schwann cells have been proposed as a potential treatment strategy for peripheral demyelinating diseases. However, strategies developed to date primarily focussed on either remyelination or oxidative stress in isolation. Here, we have developed a multifunctional nanofibrous scaffold with material and biochemical cues to tackle both remyelination and oxidative stress in one matrix. We developed a nanofibrous scaffold using polycaprolactone (PCL) as a foundation loaded with antioxidant graphene oxide (GO) and coated this bioscaffold with Schwann cell acellular matrix. In vitro studies revealed both antioxidant and remyelination properties of the developed bioscaffold. Based on the results, the developed multifunctional bioscaffold approach can be a promising biomaterial approach for treating demyelinating diseases.

Dramatic Response to Anti-IL-6 Receptor Therapy in Children With Life-Threatening Myelin Oligodendrocyte Glycoprotein-Associated Disease.

OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an immune-mediated neuroinflammatory disorder leading to demyelination of the CNS. Interleukin (IL)-6 receptor blockade is under study in relapsing MOGAD as a preventative strategy, but little is known about the role of such treatment for acute MOGAD attacks. METHODS: We discuss the cases of a 7-year-old boy and a 15-year-old adolescent boy with severe acute CNS demyelination and malignant cerebral edema with early brain herniation associated with clearly positive serum titers of MOG-IgG, whose symptoms were incompletely responsive to standard acute therapies (high-dose steroids, IV immunoglobulins (IVIGs), and therapeutic plasma exchange). RESULTS: Both boys improved quickly with IL-6 receptor inhibition, administered as tocilizumab. Both patients have experienced remarkable neurologic recovery. DISCUSSION: We propose that IL-6 receptor therapies might also be considered in acute severe life-threatening presentations of MOGAD.

Monophasic Acquired Demyelinating Syndromes of the Central Nervous System in Children.

Acquired demyelinating syndromes of the central nervous system are immune-mediated demyelinating disorders that can affect the brain, optic nerves, and spinal cord. These disorders have become increasingly recognized in children due to advances in imaging techniques, improvements in diagnostic testing, extensive research into understanding the pathophysiology underlying these disorders, and collaborative multi-institutional efforts to raise awareness of these disorders in children. Moreover, developments in the field of neuroimmunology have allowed us to identify autoantibodies that have presumed causal roles in acquired demyelinating syndromes. Identification of these autoantibodies helps determine clinical course (ie, monophasic vs relapsing course), prognosis, and treatment approach. Acquired demyelinating disorders can affect both children and adults. However, the clinical features, disease course, and treatments are often unique in the pediatric population. Thus, it is important to understand the spectrum of these disorders in children to help provide a timely diagnosis and prompt treatment to achieve optimal outcomes. In this article, the epidemiology, clinical features, diagnosis, treatment, and outcomes of the most common monophasic acquired demyelinating syndromes in children will be reviewed.

Effects of Bone Marrow Mesenchymal Stem Cells on Myelin Repair and Emotional Changes of a Cuprizone-Induced Demyelination Model.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease for which bone marrow mesenchymal stem cells (BM-MSCs) have become one of the most promising tools for treatment. Cuprizone(CPZ) induces demyelination in the central nervous system and its use has established a demyelination sheath animal model which is particularly suitable for studying the effects of BM-MSCs on the remyelination and mood improvement of a demyelinating model mice. METHODS: 70 C57BL/6 male mice were selected and divided into 4 groups: the normal control (n = 20), chronic demyelination (n = 20), myelin repair (n = 15) and cell-treated groups (n = 15). Mice in the normal control group were given a normal diet; the chronic demyelination group mice were given a 0.2% CPZ mixed diet for 14 weeks, mice in the myelin repair and cell-treated groups mice were given a 0.2% CPZ diet for 12 weeks and normal diet for 2 weeks, while the cell-treated group mice were injected with BM-MSCs from the 13th week. The cuprizone-induced demyelination model was successfully established and BM-MSCs extracted, behavioural changes of the mice were detected by open field test, elevated plus maze test and tail suspension test, demyelination and repair of the corpus callosum and astrocyte changes were observed by immunofluorescence and electron microscopy and the concentrations of monoamine neurotransmitters and their metabolites detected by enzyme-linked immunosorbent assay (ELISA) and high performance liquid chromatography-electrochemistry (HPLC-ECD). RESULTS: Results suggest BM-MSCs were successfully extracted and cultured, and migrated to the demyelinating area of brain tissue after cell transplantation. Compared with the normal control group, the mice in the chronic demyelination group showed obvious anxiety and depression behaviours (p < 0.05); compared with the chronic demyelination group, the anxiety and depression behaviours of the cell-treated group mice were improved (p < 0.05); compared with the normal control group, the demyelination of the corpus callosum region of the chronic demyelination group mice was significant (p < 0.01), while the myelin sheath of the cell-treated and myelin repair groups was repaired when compared with the chronic demyelination group (p < 0.05), and the cell-treated group had a more significant effect than the myelin repair group (p < 0.05). Compared with the normal control group, the number of astrocytes in the corpus callosum of the chronic demyelination group mice was significantly increased (p < 0.01), and the expression of glial fibrillary acidic protein (GFAP) in the cell-treated group was lower than that in the chronic demyelination and myelin repair groups (p < 0.05); the serum concentrations of norepinephrine (NE), 5-hydroxytryptamine (5-HT) and 5-Hydroxyindole-3-acetic acid (5-HIAA) between the normal control and the chronic demyelination groups were significantly different (p < 0.05). CONCLUSIONS: The CPZ-induced model can be used as an experimental carrier for MS combined with anxiety and depression, and BM-MSC transplantation promotes the repair of myelin sheath and the recovery of emotional disorders in the model.

The Journey of iPSC-derived OPCs in Demyelinating Disorders: From In vitro Generation to In vivo Transplantation.

Loss of myelination is common among neurological diseases. It causes significant disability, even death, if it is not treated instantly. Different mechanisms involve the pathophysiology of demyelinating diseases, such as genetic background, infectious, and autoimmune inflammation. Recently, regenerative medicine and stem cell therapy have shown to be promising for the treatment of demyelinating disorders. Stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and adult stem cells (ASCs), can differentiate into oligodendrocyte progenitor cells (OPCs), which may convert to oligodendrocytes (OLs) and recover myelination. IPSCs provide an endless source for OPCs generation. However, the restricted capacity of proliferation, differentiation, migration, and myelination of iPSC-derived OPCs is a notable gap for future studies. In this article, we have first reviewed stem cell therapy in demyelinating diseases. Secondly, methods of different protocols have been discussed among in vitro and in vivo studies on iPSC-derived OPCs to contrast OPCs' transplantation efficacy. Lastly, we have reviewed the results of iPSCs-derived OLs production in each demyelination model.

Cell reprogramming for oligodendrocytes: A review of protocols and their applications to disease modeling and cell-based remyelination therapies.

Oligodendrocytes are a type of glial cells that produce a lipid-rich membrane called myelin. Myelin assembles into a sheath and lines neuronal axons in the brain and spinal cord to insulate them. This not only increases the speed and efficiency of nerve signal transduction but also protects the axons from damage and degradation, which could trigger neuronal cell death. Demyelination, which is caused by a loss of myelin and oligodendrocytes, is a prominent feature of many neurological conditions, including Multiple sclerosis (MS), spinal cord injuries (SCI), and leukodystrophies. Demyelination is followed by a time of remyelination mediated by the recruitment of endogenous oligodendrocyte precursor cells, their migration to the injury site, and differentiation into myelin-producing oligodendrocytes. Unfortunately, endogenous remyelination is not sufficient to overcome demyelination, which explains why there are to date no regenerative-based treatments for MS, SCI, or leukodystrophies. To better understand the role of oligodendrocytes and develop cell-based remyelination therapies, human oligodendrocytes have been derived from somatic cells using cell reprogramming. This review will detail the different cell reprogramming methods that have been developed to generate human oligodendrocytes and their applications to disease modeling and cell-based remyelination therapies. Recent developments in the field have seen the derivation of brain organoids from pluripotent stem cells, and protocols have been devised to incorporate oligodendrocytes within the organoids, which will also be reviewed.

Magnetization transfer ratio for assessing remyelination after transcranial ultrasound stimulation in the lysolecithin rat model of multiple sclerosis.

It has been shown that transcranial ultrasound stimulation (TUS) is capable of attenuating myelin loss and providing neuroprotection in animal models of brain disorders. In this study, we investigated the ability of TUS to promote remyelination in the lysolecithin (LPC)-induced local demyelination in the hippocampus. Demyelination was induced by the micro-injection of 1.5 µL LPC (1%) into the rat hippocampus and the treated group received daily TUS for 5 or 12 days. Magnetic resonance imaging techniques, including magnetization transfer ratio (MTR) and T2-weighted imaging, were used to longitudinally characterize the demyelination model. Furthermore, the therapeutic effects of TUS on LPC-induced demyelination were assessed by Luxol fast blue (LFB) staining. Our data revealed that reductions in MTR values observed during demyelination recover almost completely upon remyelination. The MTR values in demyelinated lesions were significantly higher in TUS-treated rats than in the LPC-only group after undergoing TUS. Form histological observation, TUS significantly reduced the size of demyelinated lesion 7 days after LPC administration. This study demonstrated that MTR was a sensitive and reproducible quantitative marker to assess remyelination process in vivo during TUS treatment. These findings might open new promising treatment strategies for demyelinating diseases such as multiple sclerosis.

Effects of hyperbaric oxygen on Notch signaling pathway after severe carbon monoxide poisoning in mice.

Demyelination of the cerebral white matter is the most common pathological change after carbon monoxide (CO) poisoning. Notch signaling, the mechanism underlying the differentiation of astrocytes and oligodendrocytes, is critical to remyelination of the white matter after brain lesion. The purpose of this work was to determine the effects of hyperbaric oxygen (HBO) on Notch signaling pathway after CO poisoning for the explanation of the protective effects of HBO on CO-poisoning-related cerebral white matter demyelination. The male C57 BL/6 mice with severe CO poisoning were treated by HBO. And HBO therapy shortened the escape latency and improved the body mass after CO poisoning. HBO therapy also significantly suppressed protein and mRNA levels of Notch1 and Hes5 after CO poisoning. Our findings suggested that HBO could suppress the activation of Notch signaling pathway after CO poisoning, which is the mechanism underlying the neuroprotection of HBO on demyelination after severe CO poisoning.

[Osmotic demyelination syndrome and overly rapid correction of hyponatremia]. / Syndrome de démyélinisation osmotique : quelle vitesse de correction de la natrémie ?

Hyponatremia is a frequent condition in hospitalized patients and is associated with significant morbidity and mortality. An association between rapid correction of hyponatremia and the occurrence of osmotic demyelination syndrome has been reported. Osmotic demyelination syndrome may present with severe neurologic symptoms, including in rare cases locked-in. Therefore, rapid correction of hyponatremia is recommended only in the presence of severe symptoms. In those cases, hypertonic saline (NaCl 3% 2 ml/Kg over 20 minutes) is recommended with close plasma sodium monitoring. After symptoms improvement, increases in sodium concentration should not exceed 8 mmol/l/24h. In cases without severe neurologic symptoms, the use of 3% NaCl solution should be avoided, and management should target the underlying causes of hyponatremia.

L'hyponatrémie est fréquente à l'hôpital avec une morbimortalité significative. Une association entre la vitesse de correction d'une hyponatrémie et la survenue d'un syndrome de démyélinisation osmotique (SDO) a été mise en évidence dans des études observationnelles. Dès lors, une correction rapide d'une hyponatrémie doit être réservée aux patients avec des symptômes sévères d'hyponatrémie. Dans ces situations, l'utilisation de NaCl 3 % (2 ml/kg) en bolus est recommandée avec des contrôles rapprochés de la natrémie. Après l'amélioration des symptômes, une vitesse de correction inférieure à 8 mmol/24 heures est indiquée. En l'absence de symptômes sévères, il est préférable d'éviter l'utilisation du NaCl 3 % et de traiter selon le mécanisme sous-jacent.

Combination Therapy of Mesenchymal Stem Cell Transplantation and Astrocyte Ablation Improve Remyelination in a Cuprizone-Induced Demyelination Mouse Model.

Astrocytes display an active, dual, and controversial role in multiple sclerosis (MS), a chronic inflammatory demyelination disorder. However, mesenchymal stem cells (MSCs) can affect myelination in demyelinating disorders. This study aimed to investigate the effect of single and combination therapies of astrocyte ablation and MSC transplantation on remyelination in the cuprizone (CPZ) model of MS. C57BL/6 mice were fed 0.2% CPZ diet for 12 weeks. Astrocytes were ablated twice by L-a-aminoadipate (L-AAA) at the beginning of weeks 13 and 14 whereas MSCs were injected in the corpus callosum at the beginning of week 13. Motor coordination and balance were assessed through rotarod test whereas myelin content was evaluated by Luxol-fast blue (LFB) staining and transmission electron microscopy (TEM). Glial cells were assessed by immunofluorescence staining while mRNA expression was evaluated by quantitative real-time PCR. Combination treatment of ablation of astrocytes and MSC transplantation (CPZ + MSC + L-AAA) significantly decreased motor coordination deficits better than single treatments (CPZ + MSCs or CPZ + L-AAA), in comparison to CPZ mice. In addition, L-AAA and MSCs treatment significantly enhanced remyelination compared to CPZ group. Moreover, combination therapy caused a significant decrease in the number of GFAP+ and Iba-1+ cells, whereas oligodendrocytes were significantly increased in comparison to CPZ mice. Finally, MSC administration resulted in a significant upregulation of BDNF and NGF mRNA expression levels. Our data indicate that transient ablation of astrocytes along with MSCs treatment improve remyelination through enhancing oligodendrocytes and attenuating gliosis in a chronic demyelinating mouse model of MS.

Glial Response to Intranasal Mesenchymal Stem Cells in Intermittent Cuprizone Model of Demyelination.

Intranasal mesenchymal stem cells (MSCs) delivery is a non-invasive method that has received interests for treatment of neurodegenerative diseases, such as multiple sclerosis (MS). The impact of intranasal MSCs on intermittent cuprizone model of demyelination was a focus of this study. C57/BL6 mice were fed with 0.3% cuprizone in an intermittent or single ways. Luxol fast blue (LFB), Rotarod test, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and western blot (WB) were used for interpretation of outcomes. MSCs effectively homed to the corpus callosum area, were able to improve motor coordination and to promote myelin recovery in the intermittent cuprizone (INTRCPZ/MSCs). Astrogliosis (GFAP+ cells) and microgliosis (Iba-1+ cells) were hampered, and more mature oligodendrocyte cells (APC+ cells) were identified in mice receiving INTRCPZ/MSCs. Such treatment also considerably reduced markers related to the macrophage type 1 (M1) cells, namely iNOS and CD86, but it recovered the M2 markers MRC-1 and TREM-2. In addition, a remarkable decrease in the expressions of pro-inflammatory IL-1ß and TNFα but an increase in the rate of anti-inflammatory TGF-ß and IL-10 were identified in mice that underwent INTRCPZ/MSCs therapy. Finally, microvascular changes were evaluated, and a noticeable increase in the expression of the endothelial cell marker CD31 was found in the INTRCPZ/MSCs-treated mice (p < 0.05 for all). The outcomes are representative of the efficacy of intranasal MSCs delivery in intermittent cuprizone model of MS for reshaping macrophage polarity along with modification of glial, inflammatory, and angiogenic markers in favor of therapy.