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Glia Oct 2020Remyelination, namely, the formation of new myelin sheaths around denuded axons, counteracts axonal degeneration and restores neuronal function. Considerable advances... (Review)
Review
Remyelination, namely, the formation of new myelin sheaths around denuded axons, counteracts axonal degeneration and restores neuronal function. Considerable advances have been made in understanding this regenerative process that often fails in diseases like multiple sclerosis, leaving axons demyelinated and vulnerable to damage, thus contributing to disease progression. The identification of the membrane receptor GPR17 on a subset of oligodendrocyte precursor cells (OPCs), which mediate remyelination in the adult central nervous system (CNS), has led to a huge amount of evidence that validated this receptor as a new attractive target for remyelinating therapies. Here, we summarize the role of GPR17 in OPC function, myelination and remyelination, describing its atypical pharmacology, its downstream signaling, and the genetic and epigenetic factors modulating its activity. We also highlight crucial insights into GPR17 pathophysiology coming from the demonstration that oligodendrocyte injury, associated with inflammation in chronic neurodegenerative conditions, is invariably characterized by abnormal and persistent GPR17 upregulation, which, in turn, is accompanied by a block of OPCs at immature premyelinating stages. Finally, we discuss the current literature in light of the potential exploitment of GPR17 as a therapeutic target to promote remyelination.
Topics: Animals; Demyelinating Diseases; Epigenesis, Genetic; Humans; Myelin Sheath; Oligodendroglia; Receptors, G-Protein-Coupled; Remyelination; Signal Transduction
PubMed: 32086854
DOI: 10.1002/glia.23807 -
NeuroImage. Clinical 2015Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures... (Review)
Review
Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI) and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1) pediatric demyelinating conditions affecting the spinal cord; (2) their distinguishing features; and (3) current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis.
Topics: Child; Child, Preschool; Demyelinating Diseases; Humans; Neuroimaging; Pain; Spinal Cord
PubMed: 26509120
DOI: 10.1016/j.nicl.2015.08.019 -
Veterinary Pathology Jan 2018Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous... (Review)
Review
Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous system (CNS). These include multiple sclerosis (MS), the most common chronic IIDD, but also rarer disorders such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO). Great efforts have been made to understand the pathophysiology of MS, leading to the development of a few effective treatments. Nonetheless, IIDD still require a better understanding of the causes and underlying mechanisms to implement more effective therapies and diagnostic methods. Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model to study the pathophysiology of IIDD. EAE is principally induced through immunization with myelin antigens combined with immune-activating adjuvants. Nonhuman primates (NHP), the phylogenetically closest relatives of humans, challenged by similar microorganisms as other primates may recapitulate comparable immune responses to that of humans. In this review, the authors describe EAE models in 3 NHP species: rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), and common marmosets ( Callithrix jacchus), evaluating their respective contribution to the understanding of human IIDD. EAE in NHP is a heterogeneous disease, including acute monophasic and chronic polyphasic forms. This diversity makes it a versatile model to use in translational research. This clinical variability also creates an opportunity to explore multiple facets of immune-mediated mechanisms of neuro-inflammation and demyelination as well as intrinsic protective mechanisms. Here, the authors review current insights into the pathogenesis and immunopathological mechanisms implicated in the development of EAE in NHP.
Topics: Animals; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Nervous System Autoimmune Disease, Experimental; Primates
PubMed: 28583039
DOI: 10.1177/0300985817712794 -
Multiple Sclerosis and Related Disorders Dec 2023To explore the clinical characteristics, immunotherapy response, and prognosis of pediatric anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis associated with...
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.
Topics: Humans; Child; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Retrospective Studies; Autoantibodies; Neoplasm Recurrence, Local; Myelin-Oligodendrocyte Glycoprotein; Brain; Magnetic Resonance Imaging; Syndrome; Demyelinating Diseases; Recurrence; Immunoglobulin G
PubMed: 37913674
DOI: 10.1016/j.msard.2023.105063 -
Journal of Neurology, Neurosurgery, and... Dec 2014Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are... (Review)
Review
Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are feasible from a time and practicality point of view, as well as being sensitive and specific to myelin, while also being reproducible and clinically meaningful. Conventional MRI sequences have limited specificity for myelination. We evaluate the imaging modalities which are potentially more specific to myelin content in vivo, such as magnetisation transfer ratio (MTR), restricted proton fraction f (from quantitative magnetisation transfer measurements), myelin water fraction and diffusion tensor imaging (DTI) metrics, in addition to positron emission tomography (PET) imaging. Although most imaging applications to date have focused on the brain, we also consider measures with the potential to detect remyelination in the spinal cord and in the optic nerve. At present, MTR and DTI measures probably offer the most realistic and feasible outcome measures for such trials, especially in the brain. However, no one measure currently demonstrates sufficiently high sensitivity or specificity to myelin, or correlation with clinical features, and it should be useful to employ more than one outcome to maximise understanding and interpretation of findings with these sequences. PET may be less feasible for current and near-future trials, but is a promising technique because of its specificity. In the optic nerve, visual evoked potentials can indicate demyelination and should be correlated with an imaging outcome (such as optic nerve MTR), as well as clinical measures.
Topics: Clinical Trials as Topic; Demyelinating Diseases; Diffusion Tensor Imaging; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Neuroimaging; Positron-Emission Tomography; Treatment Outcome
PubMed: 24769473
DOI: 10.1136/jnnp-2014-307650 -
Journal of Neuroimmunology Jul 2017Neurotropic viruses are important causes of morbidity and mortality in human populations. Some of these viruses preferentially infect oligodendrocytes in the white... (Review)
Review
Neurotropic viruses are important causes of morbidity and mortality in human populations. Some of these viruses preferentially infect oligodendrocytes in the white matter, causing either direct lysis of infected cells, or more commonly myelin damage as a consequence of the host immune response to the virus. Virus-induced demyelination has similarities to the human disease multiple sclerosis. To study this disease process in experimental animals, mice are infected, most commonly, with neurotropic strains of mouse hepatitis virus, a coronavirus or Theiler's murine encephalomyelitis, a picornavirus. While the diseases caused by these two viruses differ in some aspects, in both cases demyelination is a major consequence of the infection. As in autoimmune disease, therapeutic interventions that diminish an overactive immune response would be useful. However, unlike autoimmune disease, complete suppression would result in unchecked virus replication, generally leading to more severe disease. Here we discuss two approaches that dampen but do not fully suppress the host immune response. Regulatory T cells, especially those that are specific for antigens recognized by pathogenic T cells, and IL-10 are two anti-inflammatory/pro-resolution factors that demonstrate efficacy in experimental models of virus-induced demyelination and may be useful in patients infected with viruses that cause demyelination.
Topics: Animals; Demyelinating Diseases; Humans; Interleukin-10; T-Lymphocytes, Regulatory; Virus Diseases
PubMed: 28065579
DOI: 10.1016/j.jneuroim.2017.01.001 -
Multiple Sclerosis (Houndmills,... Feb 2020
Topics: Brain; Demyelinating Diseases; Humans; Meninges; Multiple Sclerosis
PubMed: 32052711
DOI: 10.1177/1352458519892186 -
Journal of Neuroscience Research Dec 2018Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of unknown etiology. Both genetic-susceptibility and environment exposures, including vitamin D... (Review)
Review
Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of unknown etiology. Both genetic-susceptibility and environment exposures, including vitamin D deficiency, Epstein-Barr viral and Herpesvirus (HHV-6) infections are strongly implicated in the activation of T cells and MS-pathogenesis. Despite precise knowledge of how these factors could be operating alone or in combination to facilitate and aggravate the disease progression, it is clear that prolonged induction of inflammatory molecules and recruitment of other immune cells by the activated T cells results in demyelination and axonal damage. It is imperative to understand the risk factors associated with MS progression and how these factors contribute to disease pathology. Understanding of the underlying mechanisms of what factors triggers activation of T cells to attack myelin antigen are important to strategize therapeutics and therapies against MS. Current review provides a detailed literature to understand the role of both pathogenic and non-pathogenic factors on the impact of MS.
Topics: Animals; Demyelinating Diseases; Genetic Predisposition to Disease; Models, Animal; Multiple Sclerosis; Signal Transduction
PubMed: 30204260
DOI: 10.1002/jnr.24322 -
Experimental Neurology Sep 2016There is an increasing number of neurologic disorders found to be associated with loss and/or dysfunction of the CNS myelin sheath, ranging from the classic... (Review)
Review
There is an increasing number of neurologic disorders found to be associated with loss and/or dysfunction of the CNS myelin sheath, ranging from the classic demyelinating disease, multiple sclerosis, through CNS injury, to neuropsychiatric diseases. The disabling burden of these diseases has sparked a growing interest in gaining a better understanding of the molecular mechanisms regulating the differentiation of the myelinating cells of the CNS, oligodendrocytes (OLGs), and the process of (re)myelination. In this context, the importance of the extracellular milieu is becoming increasingly recognized. Under pathological conditions, changes in inhibitory as well as permissive/promotional cues are thought to lead to an overall extracellular environment that is obstructive for the regeneration of the myelin sheath. Given the general view that remyelination is, even though limited in human, a natural response to demyelination, targeting pathologically 'dysregulated' extracellular cues and their downstream pathways is regarded as a promising approach toward the enhancement of remyelination by endogenous (or if necessary transplanted) OLG progenitor cells. In this review, we will introduce the extracellular cues that have been implicated in the modulation of (re)myelination. These cues can be soluble, part of the extracellular matrix (ECM) or mediators of cell-cell interactions. Their inhibitory and permissive/promotional roles with regard to remyelination as well as their potential for therapeutic intervention will be discussed.
Topics: Animals; Cell Differentiation; Demyelinating Diseases; Extracellular Matrix; Humans; Nerve Regeneration; Oligodendroglia; Stem Cells
PubMed: 27016069
DOI: 10.1016/j.expneurol.2016.03.019 -
Neurotoxicology Mar 2021In the central and peripheral nervous systems, myelin is essential for efficient conduction of action potentials. During development, oligodendrocytes and Schwann cells... (Review)
Review
In the central and peripheral nervous systems, myelin is essential for efficient conduction of action potentials. During development, oligodendrocytes and Schwann cells differentiate and ensure axon myelination, and disruption of these processes can contribute to neurodevelopmental disorders. In adults, demyelination can lead to important disabilities, and recovery capacities by remyelination often decrease with disease progression. Among environmental chemical pollutants, endocrine disrupting chemicals (EDCs) are of major concern for human health and are notably suspected to participate in neurodevelopmental and neurodegenerative diseases. In this review, we have combined the current knowledge on EDCs impacts on myelin including several persistent organic pollutants, bisphenol A, triclosan, heavy metals, pesticides, and nicotine. Besides, we presented several other endocrine modulators, including pharmaceuticals and the phytoestrogen genistein, some of which are candidates for treating demyelinating conditions but could also be deleterious as contaminants. The direct impacts of EDCs on myelinating cells were considered as well as their indirect consequences on myelin, particularly on immune mechanisms associated with demyelinating conditions. More studies are needed to describe the effects of these compounds and to further understand the underlying mechanisms in relation to the potential for endocrine disruption.
Topics: Animals; Demyelinating Diseases; Endocrine Disruptors; Environmental Pollutants; Humans; Myelin Sheath; Neurotoxicity Syndromes; Prognosis; Risk Assessment; Risk Factors
PubMed: 33352275
DOI: 10.1016/j.neuro.2020.12.009