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Mechanisms of Action of Therapies for Multiple Sclerosis

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 33652

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Special Issue Editors

Dr. Manuel Comabella

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Guest Editor

Neurology Department, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d’Hebron Hospital, 08035 Barcelona, Spain
Interests: multiple sclerosis; neuromyelitis optica spectrum disorders; myelin oligodendrocyte glycoprotein associated disease; biomarkers; omics studies; neuroinflammation; mechanisms of action related with monoclonal antibodies and oral therapies

Dr. Nicolás Fissolo

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Guest Editor

Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Interests: understanding the basis of multiple sclerosis in order to identify new biomarkers to be implemented into clinical practice, and searching for new therapeutic approaches

Special Issue Information

Dear Colleagues,

In recent years, the number of treatment options for multiple sclerosis (MS) patients has grown significantly and includes (i) sphingosine 1-phosphate modulators (fingolimod, siponimod, ozanimod and ponesimod), (ii) oral therapies (teriflunomide, dimethyl fumarate), (iii) Bruton’s tyrosine kinase inhibitors (evobrutinib and tolebrutinib), and (iv) cell-depleting therapies such as cladribine, anti-CD20 monoclonal antibodies (ocrelizumab, ofatumumab), and anti-CD52 monoclonal antibodies (alemtuzumab). Each of these therapies has a distinct mechanism of action that may explain the beneficial effects of the drug in the disease, ranging from different degrees of immunomodulation to significant cell depletion. Manuscripts addressing the topic of the mechanism of action of the abovementioned therapies for MS are invited for this Special Issue. They can include but should not be restricted to in vitro and ex vivo immunophenotyping studies as well as omics approaches in peripheral blood and cerebrospinal fluid samples from treated MS patients. Studies relating changes in biomarker levels and the therapeutic response to therapies are also welcome.

Prof. Dr. Manuel Comabella
Dr. Nicolás Fissolo
Guest Editors

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Keywords

Multiple sclerosis

Therapies

Disease-modifying therapies

Mechanism of action

Immunomodulation

Cell depletion

Published Papers (7 papers)

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Research

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28 pages, 4495 KiB

Open AccessArticle

Forskolin, an Adenylcyclase/cAMP/CREB Signaling Activator Restoring Myelin-Associated Oligodendrocyte Destruction in Experimental Ethidium Bromide Model of Multiple Sclerosis

by Tarun Kapoor, Sidharth Mehan, Manisha Suri, Nidhi Sharma, Nitish Kumar, Acharan S. Narula, Abdulrahman Alshammari, Abdullah F. Alasmari, Metab Alharbi, Mohammed A. Assiri and Reni Kalfin

Cells 2022, 11(18), 2771; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11182771 - 6 Sep 2022

Cited by 7 | Viewed by 2910

Abstract

Multiple sclerosis (MS) is a chronic neurodegenerative disease marked by oligodendrocyte loss, which results in central neuronal demyelination. AC/cAMP/CREB signaling dysregulation is involved in the progression of MS, including mitochondrial dysfunctions, reduction in nerve growth factors, neuronal inflammation, apoptosis, and white matter degeneration. Our previous research has shown that Forskolin (FSK), a naturally occurring direct adenylyl cyclase (AC)/cAMP/CREB activator, has neuroprotective potential to alleviate pathogenic factors linked with numerous neurological abnormalities. The current study intends to explore the neuroprotective potential of FSK at doses of 40 mg/kg and 60 mg/kg alone, as well as in combination with conventional medicines, such as Fingolimod (FNG), Donepezil (DON), Memantine (MEM), and Simvastatin (SIM) in EB-induced demyelinated experimental MS rats. Adult Wistar rats were divided into nine groups, and EB was infused stereotaxically in the rat brain’s intracerebropeduncle (ICP) area. Chronic gliotoxin EB treatment results in demyelination as well as motor and cognitive dysfunctions. FSK, combined with standard medications, improves behavioral dysfunctions, such as neuromuscular and motor deficits and memory and cognitive abnormalities. Following pharmacological treatments improved remyelination by enhancing myelin basic protein and increasing AC, cAMP, and CREB levels in brain homogenates. Furthermore, FSK therapy restored brain mitochondrial-ETC complex enzymes and neurotransmitter levels while decreasing inflammatory cytokines and oxidative stress markers. The Luxol fast blue (LFB) stain results further indicate FSK’s neuroprotective potential in preventing oligodendrocyte death. Therefore, the results of these studies contribute to a better understanding of the possible role that natural phytochemicals FSK could have in preventing motor neuron diseases, such as multiple sclerosis. Full article

(This article belongs to the Special Issue Mechanisms of Action of Therapies for Multiple Sclerosis)

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21 pages, 2834 KiB

Open AccessArticle

Ocrelizumab in Patients with Active Primary Progressive Multiple Sclerosis: Clinical Outcomes and Immune Markers of Treatment Response

by Marina Boziki, Christos Bakirtzis, Styliani-Aggeliki Sintila, Evangelia Kesidou, Evdoxia Gounari, Aliki Ioakimidou, Vasiliki Tsavdaridou, Lemonia Skoura, Asimina Fylaktou, Vasiliki Nikolaidou, Maria Stangou, Ioannis Nikolaidis, Virginia Giantzi, Eleni Karafoulidou, Paschalis Theotokis and Nikolaos Grigoriadis

Cells 2022, 11(12), 1959; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11121959 - 17 Jun 2022

Cited by 3 | Viewed by 3095

Abstract

Ocrelizumab is a B-cell-depleting monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) and active primary progressive MS (aPPMS). This prospective, uncontrolled, open-label, observational study aimed to assess the efficacy of ocrelizumab in patients with aPPMS and to dissect the clinical, radiological and laboratory attributes of treatment response. In total, 22 patients with aPPMS followed for 24 months were included. The primary efficacy outcome was the proportion of patients with optimal response at 24 months, defined as patients free of relapses, free of confirmed disability accumulation (CDA) and free of T1 Gd-enhancing lesions and new/enlarging T2 lesions on the brain and cervical MRI. In total, 14 (63.6%) patients and 13 patients (59.1%) were classified as responders at 12 and 24 months, respectively. Time exhibited a significant effect on mean absolute and normalized gray matter cerebellar volume (F = 4.342, p = 0.23 and F = 4.279, p = 0.024, respectively). Responders at 24 months exhibited reduced peripheral blood ((%) of CD19+ cells) plasmablasts compared to non-responders at the 6-month point estimate (7.69 ± 4.4 vs. 22.66 ± 7.19, respectively, p = 0.043). Response to ocrelizumab was linked to lower total and gray matter cerebellar volume loss over time. Reduced plasmablast depletion was linked for the first time to sub-optimal response to ocrelizumab in aPPMS. Full article

(This article belongs to the Special Issue Mechanisms of Action of Therapies for Multiple Sclerosis)

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13 pages, 1561 KiB

Open AccessArticle

Immunomodulatory Effects Associated with Cladribine Treatment

by Nicolás Fissolo, Laura Calvo-Barreiro, Herena Eixarch, Ursula Boschert, Carmen Espejo, Xavier Montalban and Manuel Comabella

Cells 2021, 10(12), 3488; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123488 - 10 Dec 2021

Cited by 14 | Viewed by 2940

Abstract

Cladribine is a synthetic deoxyadenosine analogue with demonstrated efficacy in patients with relapsing-remitting multiple sclerosis (MS). The main mechanism of action described for cladribine is the induction of a cytotoxic effect on lymphocytes, leading to a long-term depletion of peripheral T and B cells. Besides lymphocyte toxicity, the mode of action may include immunomodulatory mechanisms affecting other cells of the immune system. In order to induce its beneficial effects, cladribine is phosphorylated inside the cell by deoxycytidine kinase (DCK) to its active form. However, the mechanism of action of cladribine may also include immunomodulatory pathways independent of DCK activation. This in vitro study was designed to explore the impact of cladribine on peripheral blood mononuclear cells (PBMC) subsets, and to assess whether the immunomodulatory mechanisms induced by cladribine depend on the activation of the molecule. To this end, we obtained PBMCs from healthy donors and MS patients and performed proliferation, apoptosis and activation assays with clinically relevant concentrations of cladribine in DCK-dependent and -independent conditions. We also evaluated the effect of cladribine on myeloid lineage-derived cells, monocytes and dendritic cells (DCs). Cladribine decreased proliferation and increased apoptosis of lymphocyte subsets after prodrug activation via DCK. In contrast, cladribine induced a decrease in immune cell activation through both DCK-dependent and -independent pathways (not requiring prodrug activation). Regarding monocytes and DCs, cladribine induced cytotoxicity and impaired the activation of classical monocytes, but had no effect on DC maturation. Taken together, these data indicate that cladribine, in addition to its cytotoxic function, can mediate immunomodulation in different immune cell populations, by regulating their proliferation, maturation and activation. Full article

(This article belongs to the Special Issue Mechanisms of Action of Therapies for Multiple Sclerosis)

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11 pages, 954 KiB

Open AccessArticle

Modulation of Tregs and iNKT by Fingolimod in Multiple Sclerosis Patients

by Diana Ferraro, Sara De Biasi, Anna Maria Simone, Riccardo Orlandi, Milena Nasi, Francesca Vitetta, Marcello Pinti, Marco Fogliani, Stefano Meletti, Andrea Cossarizza and Patrizia Sola

Cells 2021, 10(12), 3324; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123324 - 26 Nov 2021

Cited by 3 | Viewed by 1771

Abstract

The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS), an immune-mediated disease. We aimed to assess the frequencies of Tregs and iNKT cells in MS patients throughout a one-year treatment with fingolimod (FTY) and to correlate immunological data with efficacy and safety data. The percentage of Tregs (defined as Live Dead-CD3 + CD4 + FoxP3 + CD25++/CD127− cells) increased steadily throughout the year, while there was no significant difference in the absolute number or percentage of iNKT cells (defined as CD3 + CD14−CD19− Vα24-Jα18 TCR+ cells). However, out of all the iNKT cells, the CD8+ iNKT and CD4−CD8− double-negative (DN) cell percentages steadily increased, while the CD4+ iNKT cell percentages decreased significantly. The mean percentage of CD8+ T cells at all time-points was lower in patients with infections throughout the study. The numbers and percentages of DN iNKT cells were more elevated, considering all time-points, in patients who presented a clinical relapse. FTY may, therefore, exert its beneficial effect in MS patients through various mechanisms, including the increase in Tregs and in iNKT subsets with immunomodulatory potential such as CD8+ iNKT cells. The occurrence of infections was associated with lower mean CD8+ cell counts during treatment with FTY. Full article

(This article belongs to the Special Issue Mechanisms of Action of Therapies for Multiple Sclerosis)

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Review

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15 pages, 1655 KiB

Open AccessReview

Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway Modulators, from Current Insights to Future Perspectives

by Gary Álvarez Bravo, René Robles Cedeño, Marc Puig Casadevall and Lluís Ramió-Torrentà

Cells 2022, 11(13), 2058; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11132058 - 29 Jun 2022

Cited by 34 | Viewed by 8597

Abstract

Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are bioactive lipid molecules that are ubiquitously expressed in the human body and play an important role in the immune system. S1P-S1PR signaling has been well characterized in immune trafficking and activation in both innate and adaptive immune systems. Despite this knowledge, the full scope in the pathogenesis of autoimmune disorders is not well characterized yet. From the discovery of fingolimod, the first S1P modulator, until siponimod, the new molecule recently approved for the treatment of secondary progressive multiple sclerosis (SPMS), there has been a great advance in understanding the S1P functions and their involvement in immune diseases, including multiple sclerosis (MS). Modulation on S1P is an interesting target for the treatment of various autoimmune disorders. Improved understanding of the mechanism of action of fingolimod has allowed the development of the more selective second-generation S1PR modulators. Subtype 1 of the S1PR (S1PR1) is expressed on the cell surface of lymphocytes, which are known to play a major role in MS pathogenesis. The understanding of S1PR1’s role facilitated the development of pharmacological strategies directed to this target, and theoretically reduced the safety concerns derived from the use of fingolimod. A great advance in the MS treatment was achieved in March 2019 when the Food and Drug Association (FDA) approved Siponimod, for both active secondary progressive MS and relapsing–remitting MS. Siponimod became the first oral disease modifying therapy (DMT) specifically approved for active forms of secondary progressive MS. Additionally, for the treatment of relapsing forms of MS, ozanimod was approved by FDA in March 2020. Currently, there are ongoing trials focused on other new-generation S1PR1 modulators. This review approaches the fundamental aspects of the sphingosine phosphate modulators and their main similarities and differences. Full article

(This article belongs to the Special Issue Mechanisms of Action of Therapies for Multiple Sclerosis)

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32 pages, 3900 KiB

Open AccessReview

Lymphocyte Counts and Multiple Sclerosis Therapeutics: Between Mechanisms of Action and Treatment-Limiting Side Effects

by Stefanie Fischer, Undine Proschmann, Katja Akgün and Tjalf Ziemssen

Cells 2021, 10(11), 3177; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113177 - 15 Nov 2021

Cited by 15 | Viewed by 8811

Abstract

Although the detailed pathogenesis of multiple sclerosis (MS) is not completely understood, a broad range of disease-modifying therapies (DMTs) are available. A common side effect of nearly every MS therapeutic agent is lymphopenia, which can be both beneficial and, in some cases, treatment-limiting. A sound knowledge of the underlying mechanism of action of the selected agent is required in order to understand treatment-associated changes in white blood cell counts, as well as monitoring consequences. This review is a comprehensive summary of the currently available DMTs with regard to their effects on lymphocyte count. In the first part, we describe important general information about the role of lymphocytes in the course of MS and the essentials of lymphopenic states. In the second part, we introduce the different DMTs according to their underlying mechanism of action, summarizing recommendations for lymphocyte monitoring and definitions of lymphocyte thresholds for different therapeutic regimens. Full article

(This article belongs to the Special Issue Mechanisms of Action of Therapies for Multiple Sclerosis)

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15 pages, 1058 KiB

Open AccessFeature PaperReview

Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

by Antonio García-Merino

Cells 2021, 10(10), 2560; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102560 - 27 Sep 2021

Cited by 30 | Viewed by 4328

Abstract

B cells play a central role in the pathogenesis of multiple sclerosis (MS), as demonstrated through the success of various B cell-depleting monoclonal antibodies. Bruton’s tyrosine kinase (BTK) is a critical molecule in intracellular signaling from the receptor of B cells and receptors expressed in the cells of the innate immune system. BTK inhibitors may be a non-cell-depleting alternative to B cell modulation. In this review, the structure, signaling, and roles of BTK are reviewed among the different inhibitors assayed in animal models of MS and clinical trials. Full article

(This article belongs to the Special Issue Mechanisms of Action of Therapies for Multiple Sclerosis)

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