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Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 14375

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Special Issue Editor

Dr. Antonietta Bernardo

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Guest Editor

National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
Interests: neuroscience; neurodegenerative disease; myelination and remyelination; oligodendrocytes; signal transduction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This is a continued collection of the hot topic of Demyelinating Diseases. We already have done a successful special issue which received interesting contributions and discussions (https://www.mdpi.com/journal/ijms/special_issue/demyelinating_diseases).

Demyelinating diseases are a group of pathologies characterized by alteration of myelin, that is, the coating that wraps most of the nerve fibers of the central and peripheral nervous system, whose goal is the improvement of nerve conduction and the preservation of energy spent during action potential propagation. They are very disabling diseases, affecting million people worldwide. There are different types of demyelinating disorders, each characterized by peculiar characteristics that allow their classification. A broad classification of demyelinating diseases drawn according to their pathogenesis includes the following categories: due to immune-mediated inflammatory processes, infectious diseases, caused by metabolic disorders, and hypoxic-ischaemic forms. The myelin produced by oligodendrocytes in the central nervous system (CNS) differs, in chemical and immunological features, from that provided in the peripheral nervous system (PNS) by Schwann cells. Accordingly, some demyelinating diseases mainly affect the peripheral nerves, while others primarily affect the CNS. In most cases, however, there is no effective pharmacological treatment capable of completely restoring the normal functionality of myelin and nerve conduction.

The aim of this issue, entitled "Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0", is dual: to offer an overview on the landscape of the research devoted to deepening the knowledge on the pathogenic mechanisms involved in demyelinating diseases. To gather an ensemble of the efforts aimed at the identification and pre-clinical validation of targets for therapeutic approaches to be utilized in preventive or curing strategies to improve the quality of life of patients suffering from these severe pathologies. Experimental papers on in vitro or ex vivo models, up-to-date review articles, and commentaries are all welcome.

Dr. Antonietta Bernardo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

biomarkers
cellular and molecular biology
cell differentiation
cellular metabolism
demyelinating diseases
drug developing strategies and drug repositioning
glia cell (oligodendrocytes, astrocytes and microglia)
inflammation
lipid metabolism
mitochondria
myelination and remyelination
nuclear receptors
nutraceuticals
signal transduction mechanisms
target identification

Published Papers (9 papers)

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Research

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12 pages, 1932 KiB

Open AccessArticle

The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis

by Saskia Räuber, Moritz Förster, Julia Schüller, Alice Willison, Kristin S. Golombeck, Christina B. Schroeter, Menekse Oeztuerk, Robin Jansen, Niklas Huntemann, Christopher Nelke, Melanie Korsen, Katinka Fischer, Ruth Kerkhoff, Yana Leven, Patricia Kirschner, Tristan Kölsche, Petyo Nikolov, Mohammed Mehsin, Gelenar Marae, Alma Kokott, Duygu Pul, Julius Schulten, Niklas Vogel, Jens Ingwersen, Tobias Ruck, Marc Pawlitzki, Sven G. Meuth, Nico Melzer and David Kremer Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(2), 787; https://doi.org/10.3390/ijms25020787 - 8 Jan 2024

Viewed by 979

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) of still unclear etiology. In recent years, the search for biomarkers facilitating its diagnosis, prognosis, therapy response, and other parameters has gained increasing attention. In this regard, in a previous meta-analysis comprising 22 studies, we found that MS is associated with higher nitrite/nitrate (NOx) levels in the cerebrospinal fluid (CSF) compared to patients with non-inflammatory other neurological diseases (NIOND). However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria varied. As a follow-up to our meta-analysis, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve MS patients compared to patients with somatic symptom disorder. To this end, we analyzed the serum and CSF levels of NOx in 117 patients (71 relapsing–remitting (RR) MS, 16 primary progressive (PP) MS, and 30 somatic symptom disorder). We found that RRMS and PPMS patients had higher serum NOx levels compared to somatic symptom disorder patients. This difference remained significant in the subgroup of MRZ-negative RRMS patients. In conclusion, the measurement of NOx in the serum might indeed be a valuable tool in supporting MS diagnosis. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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34 pages, 32930 KiB

Open AccessArticle

Thalamic Neuron Resilience during Osmotic Demyelination Syndrome (ODS) Is Revealed by Primary Cilium Outgrowth and ADP-ribosylation factor-like protein 13B Labeling in Axon Initial Segment

by Jacques Gilloteaux, Kathleen De Swert, Valérie Suain and Charles Nicaise

Int. J. Mol. Sci. 2023, 24(22), 16448; https://doi.org/10.3390/ijms242216448 - 17 Nov 2023

Viewed by 1039

Abstract

A murine osmotic demyelinating syndrome (ODS) model was developed through chronic hyponatremia, induced by desmopressin subcutaneous implants, followed by precipitous sodium restoration. The thalamic ventral posterolateral (VPL) and ventral posteromedial (VPM) relay nuclei were the most demyelinated regions where neuroglial damage could be evidenced without immune response. This report showed that following chronic hyponatremia, 12 h and 48 h time lapses after rebalancing osmolarity, amid the ODS-degraded outskirts, some resilient neuronal cell bodies built up primary cilium and axon hillock regions that extended into axon initial segments (AIS) where ADP-ribosylation factor-like protein 13B (ARL13B)-immunolabeled rod-like shape content was revealed. These AIS-labeled shaft lengths appeared proportional with the distance of neuronal cell bodies away from the ODS damaged epicenter and time lapses after correction of hyponatremia. Fine structure examination verified these neuron abundant transcriptions and translation regions marked by the ARL13B labeling associated with cell neurotubules and their complex cytoskeletal macromolecular architecture. This necessitated energetic transport to organize and restore those AIS away from the damaged ODS core demyelinated zone in the murine model. These labeled structures could substantiate how thalamic neuron resilience occurred as possible steps of a healing course out of ODS. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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16 pages, 2690 KiB

Open AccessArticle

Anti-Glycolipid Antibody Examination in Five EAE Models and Theiler’s Virus Model of Multiple Sclerosis: Detection of Anti-GM1, GM3, GM4, and Sulfatide Antibodies in Relapsing-Remitting EAE

by Kota Moriguchi, Yumina Nakamura, Ah-Mee Park, Fumitaka Sato, Motoi Kuwahara, Sundar Khadka, Seiichi Omura, Ijaz Ahmad, Susumu Kusunoki and Ikuo Tsunoda

Int. J. Mol. Sci. 2023, 24(16), 12937; https://doi.org/10.3390/ijms241612937 - 18 Aug 2023

Viewed by 1658

Abstract

Anti-glycolipid antibodies have been reported to play pathogenic roles in peripheral inflammatory neuropathies, such as Guillain–Barré syndrome. On the other hand, the role in multiple sclerosis (MS), inflammatory demyelinating disease in the central nervous system (CNS), is largely unknown, although the presence of anti-glycolipid antibodies was reported to differ among MS patients with relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) disease courses. We investigated whether the induction of anti-glycolipid antibodies could differ among experimental MS models with distinct clinical courses, depending on induction methods. Using three mouse strains, SJL/J, C57BL/6, and A.SW mice, we induced five distinct experimental autoimmune encephalomyelitis (EAE) models with myelin oligodendrocyte glycoprotein (MOG)_35–55, MOG_92–106, or myelin proteolipid protein (PLP)_139–151, with or without an additional adjuvant curdlan injection. We also induced a viral model of MS, using Theiler’s murine encephalomyelitis virus (TMEV). Each MS model had an RR, SP, PP, hyperacute, or chronic clinical course. Using the sera from the MS models, we quantified antibodies against 11 glycolipids: GM1, GM2, GM3, GM4, GD3, galactocerebroside, GD1a, GD1b, GT1b, GQ1b, and sulfatide. Among the MS models, we detected significant increases in four anti-glycolipid antibodies, GM1, GM3, GM4, and sulfatide, in PLP_139–151-induced EAE with an RR disease course. We also tested cellular immune responses to the glycolipids and found CD1d-independent lymphoproliferative responses only to sulfatide with decreased interleukin (IL)-10 production. Although these results implied that anti-glycolipid antibodies might play a role in remissions or relapses in RR-EAE, their functional roles need to be determined by mechanistic experiments, such as injections of monoclonal anti-glycolipid antibodies. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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22 pages, 16877 KiB

Open AccessArticle

A Novel Ex Vivo Model to Study Therapeutic Treatments for Myelin Repair following Ischemic Damage

by Luisa Werner, Michael Gliem, Nicole Rychlik, Goran Pavic, Laura Reiche, Frank Kirchhoff, Markley Silva Oliveira Junior, Joel Gruchot, Sven G. Meuth, Patrick Küry and Peter Göttle

Int. J. Mol. Sci. 2023, 24(13), 10972; https://doi.org/10.3390/ijms241310972 - 30 Jun 2023

Viewed by 1200

Abstract

Stroke is a major reason for persistent disability due to insufficient treatment strategies beyond reperfusion, leading to oligodendrocyte death and axon demyelination, persistent inflammation and astrogliosis in peri-infarct areas. After injury, oligodendroglial precursor cells (OPCs) have been shown to compensate for myelin loss and prevent axonal loss through the replacement of lost oligodendrocytes, an inefficient process leaving axons chronically demyelinated. Phenotypic screening approaches in demyelinating paradigms revealed substances that promote myelin repair. We established an ex vivo adult organotypic coronal slice culture (OCSC) system to study repair after stroke in a resource-efficient way. Post-photothrombotic OCSCs can be manipulated for 8 d by exposure to pharmacologically active substances testing remyelination activity. OCSCs were isolated from a NG2-CreERT2-td-Tomato knock-in transgenic mouse line to analyze oligodendroglial fate/differentiation and kinetics. Parbendazole boosted differentiation of NG2⁺ cells and stabilized oligodendroglial fate reflected by altered expression of associated markers PDGFR-α, CC1, BCAS1 and Sox10 and GFAP. In vitro scratch assay and chemical ischemia confirmed the observed effects upon parbendazole treatment. Adult OCSCs represent a fast, reproducible, and quantifiable model to study OPC differentiation competence after stroke. Pharmacological stimulation by means of parbendazole promoted OPC differentiation. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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21 pages, 4690 KiB

Open AccessArticle

Seasonal Changes in Serum Metabolites in Multiple Sclerosis Relapse

by Ekaterina Martynova, Timur Khaibullin, Ilnur Salafutdinov, Maria Markelova, Alexander Laikov, Leonid Lopukhov, Rongzeng Liu, Kritika Sahay, Mehendi Goyal, Manoj Baranwal, Albert A Rizvanov and Svetlana Khaiboullina

Int. J. Mol. Sci. 2023, 24(4), 3542; https://doi.org/10.3390/ijms24043542 - 10 Feb 2023

Cited by 2 | Viewed by 1647

Abstract

Multiple sclerosis (MS) is a debilitating chronic disease of unknown etiology. There are limited treatment options due to an incomplete understanding of disease pathology. The disease is shown to have seasonal exacerbation of clinical symptoms. The mechanisms of such seasonal worsening of symptoms remains unknown. In this study, we applied targeted metabolomics analysis of serum samples using LC-MC/MC to determine seasonal changes in metabolites throughout the four seasons. We also analyzed seasonal serum cytokine alterations in patients with relapsed MS. For the first time, we can demonstrate seasonal changes in various metabolites in MS compared to the control. More metabolites were affected in MS in the fall season followed by spring, while summer MS was characterized by the smallest number of affected metabolites. Ceramides were activated in all seasons, suggesting their central role in the disease pathogenesis. Substantial changes in glucose metabolite levels were found in MS, indicating a potential shift to glycolysis. An increased serum level of quinolinic acid was demonstrated in winter MS. Histidine pathways were affected, suggesting their role in relapse of MS in the spring and fall. We also found that spring and fall seasons had a higher number of overlapping metabolites affected in MS. This could be explained by patients having a relapse of symptoms during these two seasons. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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16 pages, 2735 KiB

Open AccessArticle

Secondary Degeneration Impairs Myelin Ultrastructural Development in Adulthood following Adolescent Neurotrauma in the Rat Optic Nerve

by Brittney R. Lins, Chidozie C. Anyaegbu, Terence McGonigle, Sarah C. Hellewell, Parth Patel, Harry Reagan, Cara Rooke-Wiesner, Andrew Warnock, Michael Archer, Jan M. Hemmi, Carole Bartlett and Melinda Fitzgerald

Int. J. Mol. Sci. 2023, 24(4), 3343; https://doi.org/10.3390/ijms24043343 - 7 Feb 2023

Cited by 1 | Viewed by 1550

Abstract

Adolescence is a critical period of postnatal development characterized by social, emotional, and cognitive changes. These changes are increasingly understood to depend on white matter development. White matter is highly vulnerable to the effects of injury, including secondary degeneration in regions adjacent to the primary injury site which alters the myelin ultrastructure. However, the impact of such alterations on adolescent white matter maturation is yet to be investigated. To address this, female piebald-virol-glaxo rats underwent partial transection of the optic nerve during early adolescence (postnatal day (PND) 56) with tissue collection two weeks (PND 70) or three months later (PND 140). Axons and myelin in the transmission electron micrographs of tissue adjacent to the injury were classified and measured based on the appearance of the myelin laminae. Injury in adolescence impaired the myelin structure in adulthood, resulting in a lower percentage of axons with compact myelin and a higher percentage of axons with severe myelin decompaction. Myelin thickness did not increase as expected into adulthood after injury and the relationship between the axon diameter and myelin thickness in adulthood was altered. Notably, dysmyelination was not observed 2 weeks postinjury. In conclusion, injury in adolescence altered the developmental trajectory, resulting in impaired myelin maturation when assessed at the ultrastructural level in adulthood. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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21 pages, 2360 KiB

Open AccessArticle

Adjuvant Injections Altered the Ileal and Fecal Microbiota Differently with Changes in Immunoglobulin Isotypes and Antimycobacterial Antibody Responses

by Sundar Khadka, Seiichi Omura, Fumitaka Sato and Ikuo Tsunoda

Int. J. Mol. Sci. 2023, 24(3), 2818; https://doi.org/10.3390/ijms24032818 - 1 Feb 2023

Cited by 2 | Viewed by 1716

Abstract

Alterations in the gut microbiota, “dysbiosis,” have been reported in autoimmune diseases, including multiple sclerosis (MS), and their animal models. Although the animal models were induced by injections of autoantigens with adjuvants, including complete Freund’s adjuvant (CFA) and pertussis toxin (PT), the effects of adjuvant injections on the microbiota are largely unknown. We aimed to clarify whether adjuvant injections could affect the microbiota in the ileum and feces. Using 16S rRNA sequencing, we found decreased alpha diversities of the gut microbiota in mice injected with CFA and PT, compared with naïve mice. Overall, microbial profiles visualized by principal component analysis demonstrated dysbiosis in feces, but not in the ileum, of adjuvant-injected mice, where the genera Lachnospiraceae NK4A136 group and Alistipes contributed to dysbiosis. When we compared the relative abundances of individual bacteria, we found changes in 16 bacterial genera in feces and seven genera in the ileum of adjuvant-injected mice, in which increased serum levels of antibody against mycobacteria (a component of CFA) and total IgG2c were correlated with the genus Facklamia. On the other hand, increased IgG1 and IgA concentrations were correlated with the genus Atopostipes. Therefore, adjuvant injections alone could alter the overall microbial profiles (i.e., microbiota) and individual bacterial abundances with altered antibody responses; dysbiosis in animal models could be partly due to adjuvant injections. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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Review

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38 pages, 1067 KiB

Open AccessReview

The Heterogeneous Multiple Sclerosis Lesion: How Can We Assess and Modify a Degenerating Lesion?

by Olivia Ellen, Sining Ye, Danica Nheu, Mary Dass, Maurice Pagnin, Ezgi Ozturk, Paschalis Theotokis, Nikolaos Grigoriadis and Steven Petratos

Int. J. Mol. Sci. 2023, 24(13), 11112; https://doi.org/10.3390/ijms241311112 - 5 Jul 2023

Viewed by 2521

Abstract

Multiple sclerosis (MS) is a heterogeneous disease of the central nervous system that is governed by neural tissue loss and dystrophy during its progressive phase, with complex reactive pathological cellular changes. The immune-mediated mechanisms that promulgate the demyelinating lesions during relapses of acute episodes are not characteristic of chronic lesions during progressive MS. This has limited our capacity to target the disease effectively as it evolves within the central nervous system white and gray matter, thereby leaving neurologists without effective options to manage individuals as they transition to a secondary progressive phase. The current review highlights the molecular and cellular sequelae that have been identified as cooperating with and/or contributing to neurodegeneration that characterizes individuals with progressive forms of MS. We emphasize the need for appropriate monitoring via known and novel molecular and imaging biomarkers that can accurately detect and predict progression for the purposes of newly designed clinical trials that can demonstrate the efficacy of neuroprotection and potentially neurorepair. To achieve neurorepair, we focus on the modifications required in the reactive cellular and extracellular milieu in order to enable endogenous cell growth as well as transplanted cells that can integrate and/or renew the degenerative MS plaque. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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18 pages, 1717 KiB

Open AccessReview

Molecular, Electrophysiological, and Ultrasonographic Differences in Selected Immune-Mediated Neuropathies with Therapeutic Implications

by Edyta Dziadkowiak, Marta Nowakowska-Kotas, Wiktoria Rałowska-Gmoch, Sławomir Budrewicz and Magdalena Koszewicz

Int. J. Mol. Sci. 2023, 24(11), 9180; https://doi.org/10.3390/ijms24119180 - 24 May 2023

Viewed by 1382

Abstract

The spectrum of immune-mediated neuropathies is broad and the different subtypes are still being researched. With the numerous subtypes of immune-mediated neuropathies, establishing the appropriate diagnosis in normal clinical practice is challenging. The treatment of these disorders is also troublesome. The authors have undertaken a literature review of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Guillain–Barre syndrome (GBS) and multifocal motor neuropathy (MMN). The molecular, electrophysiological and ultrasound features of these autoimmune polyneuropathies are analyzed, highlighting the differences in diagnosis and ultimately treatment. The immune dysfunction can lead to damage to the peripheral nervous system. In practice, it is suspected that these disorders are caused by autoimmunity to proteins located in the node of Ranvier or myelin components of peripheral nerves, although disease-associated autoantibodies have not been identified for all disorders. The electrophysiological presence of conduction blocks is another important factor characterizing separate subgroups of treatment-naive motor neuropathies, including multifocal CIDP (synonyms: multifocal demyelinating neuropathy with persistent conduction block), which differs from multifocal motor neuropathy with conduction block (MMN) in both responses to treatment modalities and electrophysiological features. Ultrasound is a reliable method for diagnosing immune-mediated neuropathies, particularly when alternative diagnostic examinations yield inconclusive results. In overall terms, the management of these disorders includes immunotherapy such as corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical criteria and the development of more disease-specific immunotherapies should expand the therapeutic possibilities for these debilitating diseases. Full article

(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies 2.0)

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