International Journal of Molecular Sciences

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Open AccessEditorial

Demyelinating Diseases: From Molecular Mechanisms to Therapeutic Strategies

by Antonietta Bernardo and Sergio Visentin

Int. J. Mol. Sci. 2023, 24(5), 4596; https://doi.org/10.3390/ijms24054596 - 27 Feb 2023

Cited by 1 | Viewed by 1931

Abstract

Demyelinating diseases are a group of pathologies characterized by the alteration of myelin—that is, the coating that wraps around most of the nerve fibres of the central and peripheral nervous system, whose goal is the improvement of nerve conduction and the preservation of [...] Read more.

Demyelinating diseases are a group of pathologies characterized by the alteration of myelin—that is, the coating that wraps around most of the nerve fibres 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 [...] Full article

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

Research

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15 pages, 3678 KiB

Open AccessArticle

Tamalin Function Is Required for the Survival of Neurons and Oligodendrocytes in the CNS

by Yongbo Seo, Seojung Mo, Suhyun Kim, Hyun Kim and Hae-Chul Park

Int. J. Mol. Sci. 2022, 23(21), 13395; https://doi.org/10.3390/ijms232113395 - 2 Nov 2022

Cited by 1 | Viewed by 2376

Abstract

Tamalin is a post-synaptic scaffolding protein that interacts with group 1 metabotropic glutamate receptors (mGluRs) and several other proteins involved in protein trafficking and cytoskeletal events, including neuronal growth and actin reorganization. It plays an important role in synaptic plasticity in vitro by [...] Read more.

Tamalin is a post-synaptic scaffolding protein that interacts with group 1 metabotropic glutamate receptors (mGluRs) and several other proteins involved in protein trafficking and cytoskeletal events, including neuronal growth and actin reorganization. It plays an important role in synaptic plasticity in vitro by controlling the ligand-dependent trafficking of group 1 mGluRs. Abnormal regulation of mGluRs in the central nervous system (CNS) is associated with glutamate-mediated neurodegenerative disorders. However, the pathological consequences of tamalin deficiency in the CNS are unclear. In this study, tamalin knockout (KO) zebrafish and mice exhibited neurodegeneration along with oligodendrocyte degeneration in the post-embryonic CNS to adulthood without any developmental defects, thus suggesting the function of tamalin is more important in the postnatal stage to adulthood than that in CNS development. Interestingly, hypomyelination was independent of axonal defects in the CNS of tamalin knockout zebrafish and mice. In addition, the loss of Arf6, a downstream signal of tamalin scaffolding protein, synergistically induced neurodegeneration in tamalin KO zebrafish even in the developing CNS. Furthermore, tamalin KO zebrafish displayed increased mGluR5 expression. Taken together, tamalin played an important role in neuronal and oligodendrocyte survival and myelination through the regulation of mGluR5 in the CNS. Full article

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

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17 pages, 3729 KiB

Open AccessArticle

Effects Mediated by Dimethyl Fumarate on In Vitro Oligodendrocytes: Implications in Multiple Sclerosis

by Claudia Guerriero, Giulia Puliatti, Tamara Di Marino and Ada Maria Tata

Int. J. Mol. Sci. 2022, 23(7), 3615; https://doi.org/10.3390/ijms23073615 - 25 Mar 2022

Cited by 4 | Viewed by 3040

Abstract

Background: Dimethyl fumarate (DMF) is a drug currently in use in oral therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS) due to its immunomodulatory and neuroprotective effects. The mechanisms by which DMF exerts its therapeutic effects in MS and in particular its [...] Read more.

Background: Dimethyl fumarate (DMF) is a drug currently in use in oral therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS) due to its immunomodulatory and neuroprotective effects. The mechanisms by which DMF exerts its therapeutic effects in MS and in particular its influence on the oligodendrocytes (OLs) survival or differentiation have not yet been fully understood. Methods: Characterization of Oli neu cells was performed by immunocytochemistry and RT-PCR. The effect of DMF on cell proliferation and morphology was assessed by MTT assay, trypan blue staining, RT-PCR and Western blot analysis. The antioxidant and anti-inflammatory properties of DMF were analysed by ROS detection through DCFDA staining and lipid content analysis by Oil Red O staining and TLC. Results: DMF has been observed to induce a slowdown of cell proliferation, favoring the oligodendrocyte lineage cells (OLCs) differentiation. DMF has an antioxidant effect and is able to modify the lipid content even after the LPS-mediated inflammatory stimulus in Oli neu cells. Conclusions: The results obtained confirm that DMF has anti-inflammatory and antioxidant effects also on Oli neu cells. Interestingly, it appears to promote the OLCs differentiation towards mature and potentially myelinating cells. Full article

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

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20 pages, 6567 KiB

Open AccessArticle

The Antihypertensive Drug Telmisartan Protects Oligodendrocytes from Cholesterol Accumulation and Promotes Differentiation by a PPAR-γ-Mediated Mechanism

by Antonietta Bernardo, Mariagiovanna Malara, Lucia Bertuccini, Chiara De Nuccio, Sergio Visentin and Luisa Minghetti

Int. J. Mol. Sci. 2021, 22(17), 9434; https://doi.org/10.3390/ijms22179434 - 30 Aug 2021

Cited by 7 | Viewed by 3169

Abstract

Our previous studies have demonstrated that specific peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists play a fundamental role in oligodendrocyte progenitor (OP) differentiation, protecting them against oxidative and inflammatory damage. The antihypertensive drug Telmisartan (TLM) was shown to act as a PPAR-γ modulator. This study [...] Read more.

Our previous studies have demonstrated that specific peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists play a fundamental role in oligodendrocyte progenitor (OP) differentiation, protecting them against oxidative and inflammatory damage. The antihypertensive drug Telmisartan (TLM) was shown to act as a PPAR-γ modulator. This study investigates the TLM effect on OP differentiation and validates its capability to restore damage in a pharmacological model of Niemann-Pick type C (NPC) disease through a PPAR-γ-mediated mechanism. For the first time in purified OPs, we demonstrate that TLM-induced PPAR-γ activation downregulates the type 1 angiotensin II receptor (AT1), the level of which naturally decreases during differentiation. Like other PPAR-γ agonists, we show that TLM promotes peroxisomal proliferation and promotes OP differentiation. Furthermore, TLM can offset the OP maturation arrest induced by a lysosomal cholesterol transport inhibitor (U18666A), which reproduces an NPC1-like phenotype. In the NPC1 model, TLM also reduces cholesterol accumulation within peroxisomal and lysosomal compartments and the contacts between lysosomes and peroxisomes, revealing that TLM can regulate intracellular cholesterol transport, crucial for myelin formation. Altogether, these data indicate a new potential use of TLM in hypomyelination pathologies such as NPC1, underlining the possible repositioning of the drug already used in other pathologies. Full article

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

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18 pages, 3429 KiB

Open AccessArticle

Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress

by Dragos Paul Mihai, Anca Ungurianu, Cosmin I. Ciotu, Michael J. M. Fischer, Octavian Tudorel Olaru, George Mihai Nitulescu, Corina Andrei, Cristina Elena Zbarcea, Anca Zanfirescu, Oana Cristina Seremet, Cornel Chirita and Simona Negres

Int. J. Mol. Sci. 2021, 22(13), 7183; https://doi.org/10.3390/ijms22137183 - 2 Jul 2021

Cited by 14 | Viewed by 3913

Abstract

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake [...] Read more.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands. Full article

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

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Review

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20 pages, 1024 KiB

Open AccessReview

Role of Demyelination in the Persistence of Neurological and Mental Impairments after COVID-19

by Marina Y. Khodanovich, Daria A. Kamaeva and Anna V. Naumova

Int. J. Mol. Sci. 2022, 23(19), 11291; https://doi.org/10.3390/ijms231911291 - 25 Sep 2022

Cited by 14 | Viewed by 5737

Abstract

Long-term neurological and mental complications of COVID-19, the so-called post-COVID syndrome or long COVID, affect the quality of life. The most persistent manifestations of long COVID include fatigue, anosmia/hyposmia, insomnia, depression/anxiety, and memory/attention deficits. The physiological basis of neurological and psychiatric disorders is [...] Read more.

Long-term neurological and mental complications of COVID-19, the so-called post-COVID syndrome or long COVID, affect the quality of life. The most persistent manifestations of long COVID include fatigue, anosmia/hyposmia, insomnia, depression/anxiety, and memory/attention deficits. The physiological basis of neurological and psychiatric disorders is still poorly understood. This review summarizes the current knowledge of neurological sequelae in post-COVID patients and discusses brain demyelination as a possible mechanism of these complications with a focus on neuroimaging findings. Numerous reviews, experimental and theoretical studies consider brain demyelination as one of the mechanisms of the central neural system impairment. Several factors might cause demyelination, such as inflammation, direct effect of the virus on oligodendrocytes, and cerebrovascular disorders, inducing myelin damage. There is a contradiction between the solid fundamental basis underlying demyelination as the mechanism of the neurological injuries and relatively little published clinical evidence related to demyelination in COVID-19 patients. The reason for this probably lies in the fact that most clinical studies used conventional MRI techniques, which can detect only large, clearly visible demyelinating lesions. A very limited number of studies use specific methods for myelin quantification detected changes in the white matter tracts 3 and 10 months after the acute phase of COVID-19. Future research applying quantitative MRI assessment of myelin in combination with neurological and psychological studies will help in understanding the mechanisms of post-COVID complications associated with demyelination. Full article

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

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25 pages, 2099 KiB

Open AccessReview

Excessive Innate Immunity Steers Pathogenic Adaptive Immunity in the Development of Theiler’s Virus-Induced Demyelinating Disease

by Byung S. Kim

Int. J. Mol. Sci. 2021, 22(10), 5254; https://doi.org/10.3390/ijms22105254 - 17 May 2021

Cited by 7 | Viewed by 3382

Abstract

Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune [...] Read more.

Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/β plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1β play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3⁺CD25^- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8⁺ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses. Full article

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

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28 pages, 894 KiB

Open AccessReview

The Current Challenges for Drug Discovery in CNS Remyelination

by Sonia Balestri, Alice Del Giovane, Carola Sposato, Marta Ferrarelli and Antonella Ragnini-Wilson

Int. J. Mol. Sci. 2021, 22(6), 2891; https://doi.org/10.3390/ijms22062891 - 12 Mar 2021

Cited by 14 | Viewed by 5321

Abstract

The myelin sheath wraps around axons, allowing saltatory currents to be transmitted along neurons. Several genetic, viral, or environmental factors can damage the central nervous system (CNS) myelin sheath during life. Unless the myelin sheath is repaired, these insults will lead to neurodegeneration. [...] Read more.

The myelin sheath wraps around axons, allowing saltatory currents to be transmitted along neurons. Several genetic, viral, or environmental factors can damage the central nervous system (CNS) myelin sheath during life. Unless the myelin sheath is repaired, these insults will lead to neurodegeneration. Remyelination occurs spontaneously upon myelin injury in healthy individuals but can fail in several demyelination pathologies or as a consequence of aging. Thus, pharmacological intervention that promotes CNS remyelination could have a major impact on patient’s lives by delaying or even preventing neurodegeneration. Drugs promoting CNS remyelination in animal models have been identified recently, mostly as a result of repurposing phenotypical screening campaigns that used novel oligodendrocyte cellular models. Although none of these have as yet arrived in the clinic, promising candidates are on the way. Many questions remain. Among the most relevant is the question if there is a time window when remyelination drugs should be administrated and why adult remyelination fails in many neurodegenerative pathologies. Moreover, a significant challenge in the field is how to reconstitute the oligodendrocyte/axon interaction environment representative of healthy as well as disease microenvironments in drug screening campaigns, so that drugs can be screened in the most appropriate disease-relevant conditions. Here we will provide an overview of how the field of in vitro models developed over recent years and recent biological findings about how oligodendrocytes mature after reactivation of their staminal niche. These data have posed novel questions and opened new views about how the adult brain is repaired after myelin injury and we will discuss how these new findings might change future drug screening campaigns for CNS regenerative drugs. Full article

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

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