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Demyelinating Diseases: From Molecular Mechanisms to, Therapeutic Strategies—3rd Edition
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Demyelinating Diseases: From Molecular Mechanisms to, Therapeutic Strategies—3rd Edition

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: 20 September 2025 | Viewed by 14673

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 the third Special Issue in the continued series focused on the hot topic of demyelinating diseases. We have already launched two successful Special Issues which received interesting contributions and discussions (https://www.mdpi.com/journal/ijms/special_issue/demyelinating_diseases; https://www.mdpi.com/journal/ijms/special_issues/HZ6L4ZMBB7).

Demyelinating diseases are a group of pathologies characterized by the alteration of myelin, that is, the coating that wraps most of the nerve fibers of the central and peripheral nervous system, whose goal is to improve nerve conduction and the preservation of energy spent during action potential propagation. They are very disabling diseases, affecting millions of people worldwide. There are different types of demyelinating disorders, each characterized by peculiar characteristics that allow for their classification. A broad classification of demyelinating diseases is drawn according to their pathogenesis, including 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 terms of 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 Special Issue, entitled “Demyelinating Diseases: From Molecular Mechanisms to, Therapeutic Strategies 3.0”, is dual: to offer an overview on the landscape of research devoted to deepening knowledge on the pathogenic mechanisms involved in demyelinating diseases and 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

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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.

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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

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Published Papers (5 papers)

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Research

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19 pages, 8619 KiB  
Article
Estradiol Promotes Myelin Repair in the Spinal Cord of Female Mice in a CXCR4 Chemokine Receptor-Independent Manner
by Marianne Bardy-Lagarde, Narimene Asbelaoui, Michael Schumacher and Abdel Mouman Ghoumari
Int. J. Mol. Sci. 2025, 26(10), 4752; https://doi.org/10.3390/ijms26104752 - 15 May 2025
Abstract
In the adult central nervous system (CNS), myelin regeneration primarily occurs through the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes. In men, declining testosterone levels accelerate the progression of multiple sclerosis (MS), while in women, menopause worsens MS-related disability. We previously demonstrated [...] Read more.
In the adult central nervous system (CNS), myelin regeneration primarily occurs through the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes. In men, declining testosterone levels accelerate the progression of multiple sclerosis (MS), while in women, menopause worsens MS-related disability. We previously demonstrated that functional testes and testosterone are required for the spontaneous remyelination of a focal lysolecithin (LPC)-induced demyelinating lesion in the spinal cords of male mice. Testosterone-dependent myelin repair was dependent on the induction of the chemokine receptor CXCR4 in astrocytes that repopulated the lesion and on cooperation between androgen-receptor signaling and CXCR4 signaling. In the present study, we investigated whether ovaries and estradiol have a comparable key role in female mice. Ovariectomy prevents, the appearance of astrocytes, while treatment with estradiol enhances astrocyte numbers and promotes remyelination by oligodendrocytes within the LPC-demyelinated lesion. Unlike testosterone, estradiol did not induce CXCR4 expression, and its effects remained unaffected by the CXCR4 inhibitor AMD3100. As was seen with testosterone treatment, the presence of astrocytes and myelinating oligodendrocytes within the LPC lesion of estradiol-treated females prevented the incursion of Schwann cells. These findings highlight estradiol’s crucial role in CNS remyelination in females, providing a strong rationale for estrogen-replacement therapy in estrogen-deficient and menopausal women with MS. Full article
(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to, Therapeutic Strategies—3rd Edition)
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25 pages, 12637 KiB  
Article
Exploring the Role of Platelets in Virus-Induced Inflammatory Demyelinating Disease and Myocarditis
by Ijaz Ahmad, Seiichi Omura, Fumitaka Sato, Ah-Mee Park, Sundar Khadka, Felicity N. E. Gavins, Hiroki Tanaka, Motoko Y. Kimura and Ikuo Tsunoda
Int. J. Mol. Sci. 2024, 25(6), 3460; https://doi.org/10.3390/ijms25063460 - 19 Mar 2024
Cited by 2 | Viewed by 3080
Abstract
Theiler’s murine encephalomyelitis virus (TMEV) infection has been used as a mouse model for two virus-induced organ-specific immune-mediated diseases. TMEV-induced demyelinating disease (TMEV-IDD) in the central nervous system (CNS) is a chronic inflammatory disease with viral persistence and an animal model of multiple [...] Read more.
Theiler’s murine encephalomyelitis virus (TMEV) infection has been used as a mouse model for two virus-induced organ-specific immune-mediated diseases. TMEV-induced demyelinating disease (TMEV-IDD) in the central nervous system (CNS) is a chronic inflammatory disease with viral persistence and an animal model of multiple sclerosis (MS) in humans. TMEV infection can also cause acute myocarditis with viral replication and immune cell infiltration in the heart, leading to cardiac fibrosis. Since platelets have been reported to modulate immune responses, we aimed to determine the role of platelets in TMEV infection. In transcriptome analyses of platelets, distinct sets of immune-related genes, including major histocompatibility complex (MHC) class I, were up- or downregulated in TMEV-infected mice at different time points. We depleted platelets from TMEV-infected mice by injecting them with platelet-specific antibodies. The platelet-depleted mice had significantly fewer viral antigen-positive cells in the CNS. Platelet depletion reduced the severities of TMEV-IDD and myocarditis, although the pathology scores did not reach statistical significance. Immunologically, the platelet-depleted mice had an increase in interferon (IFN)-γ production with a higher anti-TMEV IgG2a/IgG1 ratio. Thus, platelets may play roles in TMEV infection, such as gene expression, viral clearance, and anti-viral antibody isotype responses. Full article
(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to, Therapeutic Strategies—3rd Edition)
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Review

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25 pages, 3330 KiB  
Review
Primary Progressive Multiple Sclerosis—A Key to Understanding and Managing Disease Progression
by Izabela Sempik, Edyta Dziadkowiak, Helena Moreira, Anna Zimny and Anna Pokryszko-Dragan
Int. J. Mol. Sci. 2024, 25(16), 8751; https://doi.org/10.3390/ijms25168751 - 11 Aug 2024
Cited by 2 | Viewed by 3480
Abstract
Primary progressive multiple sclerosis (PPMS), the least frequent type of multiple sclerosis (MS), is characterized by a specific course and clinical symptoms, and it is associated with a poor prognosis. It requires extensive differential diagnosis and often a long-term follow-up before its correct [...] Read more.
Primary progressive multiple sclerosis (PPMS), the least frequent type of multiple sclerosis (MS), is characterized by a specific course and clinical symptoms, and it is associated with a poor prognosis. It requires extensive differential diagnosis and often a long-term follow-up before its correct recognition. Despite recent progress in research into and treatment for progressive MS, the diagnosis and management of this type of disease still poses a challenge. Considering the modern concept of progression “smoldering” throughout all the stages of disease, a thorough exploration of PPMS may provide a better insight into mechanisms of progression in MS, with potential clinical implications. The goal of this study was to review the current evidence from investigations of PPMS, including its background, clinical characteristics, potential biomarkers and therapeutic opportunities. Processes underlying CNS damage in PPMS are discussed, including chronic immune-mediated inflammation, neurodegeneration, and remyelination failure. A review of potential clinical, biochemical and radiological biomarkers is presented, which is useful in monitoring and predicting the progression of PPMS. Therapeutic options for PPMS are summarized, with approved therapies, ongoing clinical trials and future directions of investigations. The clinical implications of findings from PPMS research would be associated with reliable assessments of disease outcomes, improvements in individualized therapeutic approaches and, hopefully, novel therapeutic targets, relevant for the management of progression. Full article
(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to, Therapeutic Strategies—3rd Edition)
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27 pages, 1342 KiB  
Review
Macrophages and HLA-Class II Alleles in Multiple Sclerosis: Insights in Therapeutic Dynamics
by Petros Prapas and Maria Anagnostouli
Int. J. Mol. Sci. 2024, 25(13), 7354; https://doi.org/10.3390/ijms25137354 - 4 Jul 2024
Cited by 3 | Viewed by 3323
Abstract
Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and the development of Multiple Sclerosis (MS). Genetic alterations within the highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes in the [...] Read more.
Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and the development of Multiple Sclerosis (MS). Genetic alterations within the highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes in the molecular basis of antigen presentation and the clinical course of patients with both Adult-Onset MS (AOMS) and Pediatric-Onset MS (POMS). Among the numerous polymorphisms of the Human Leucocyte Antigens (HLA), within MHC II complex, HLA-DRB1*15:01 has been labeled, in Caucasian ethnic groups, as a high-risk allele for MS due to the ability of its structure to increase affinity to Myelin Basic Protein (MBP) epitopes. This characteristic, among others, in the context of the trimolecular complex or immunological synapsis, provides the foundation for autoimmunity triggered by environmental or endogenous factors. As with all professional antigen presenting cells, macrophages are characterized by the expression of MHC II and are often implicated in the formation of MS lesions. Increased presence of M1 macrophages in MS patients has been associated both with progression and onset of the disease, each involving separate but similar mechanisms. In this critical narrative review, we focus on macrophages, discussing how HLA genetic alterations can promote dysregulation of this population’s homeostasis in the periphery and the Central Nervous System (CNS). We also explore the potential interconnection in observed pathological macrophage mechanisms and the function of the diverse structure of HLA alleles in neurodegenerative CNS, seen in MS, by comparing available clinical with molecular data through the prism of HLA-immunogenetics. Finally, we discuss available and experimental pharmacological approaches for MS targeting the trimolecular complex that are based on cell phenotype modulation and HLA genotype involvement and try to reveal fertile ground for the potential development of novel drugs. Full article
(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to, Therapeutic Strategies—3rd Edition)
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17 pages, 1474 KiB  
Review
The Immunomodulatory Potential of Short-Chain Fatty Acids in Multiple Sclerosis
by Laura Barcutean, Smaranda Maier, Mihai Burai-Patrascu, Lenard Farczadi and Rodica Balasa
Int. J. Mol. Sci. 2024, 25(6), 3198; https://doi.org/10.3390/ijms25063198 - 11 Mar 2024
Cited by 12 | Viewed by 4085
Abstract
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative central nervous system (CNS) disorder, characterized by focal inflammation, demyelination, irreversible axonal loss and neurodegeneration. The proposed mechanism involves auto-reactive T lymphocytes crossing the blood–brain barrier (BBB), contributing to inflammation and demyelination. Pro-inflammatory Th1 [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative central nervous system (CNS) disorder, characterized by focal inflammation, demyelination, irreversible axonal loss and neurodegeneration. The proposed mechanism involves auto-reactive T lymphocytes crossing the blood–brain barrier (BBB), contributing to inflammation and demyelination. Pro-inflammatory Th1 and Th17 lymphocytes are pivotal in MS pathogenesis, highlighting an imbalanced interaction with regulatory T cells. Dysbiosis in the gut microbiota, characterized by microbial imbalance is implicated in systemic inflammation, yet its exact role in MS remains elusive. Short-chain fatty acids (SCFAs), including valerate, butyrate, propionate, and acetate, produced through dietary fiber fermentation by the gut microbiota, modulate inflammation and immune responses. Particularly, butyrate and propionate exhibit pronounced anti-inflammatory effects in both the gut and CNS. These SCFAs influence regulatory T lymphocyte expression and BBB permeability. This review discusses the potential therapeutic implications of SCFA in MS, highlighting their ability to modulate the gut–brain axis and restore immune balance. Full article
(This article belongs to the Special Issue Demyelinating Diseases: From Molecular Mechanisms to, Therapeutic Strategies—3rd Edition)
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