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The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while...

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Autores principales: Benítez-Fernández, Rocio, Gil, Carmen, Guaza, Carmen, Mestre, Leyre, Martínez, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9694690/
https://www.ncbi.nlm.nih.gov/pubmed/36430856
http://dx.doi.org/10.3390/ijms232214378
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author Benítez-Fernández, Rocio
Gil, Carmen
Guaza, Carmen
Mestre, Leyre
Martínez, Ana
author_facet Benítez-Fernández, Rocio
Gil, Carmen
Guaza, Carmen
Mestre, Leyre
Martínez, Ana
author_sort Benítez-Fernández, Rocio
collection PubMed
description Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while protecting and repairing the nervous system are urgent. That is of utmost importance for the primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS, characterized by worsening neurological function from the onset of symptoms. In this sense, inhibitors of glycogen synthase kinase 3β (GSK3β) and phosphodiesterase 7 (PDE7) have recently shown great therapeutic potential for the treatment of demyelinating diseases. Here we investigated a dual inhibitor of these two targets, the small molecule VP3.15, in a preclinical model, which resembles primary-progressive MS (PPMS), the Theiler’s mouse encephalomyelitis virus-induced demyelinated disease (TMEV-IDD). In our study, VP3.15 ameliorates the disease course improving motor deficits of infected mice. Chronic treatment with VP3.15 also showed significant efficacy in the immunomodulation process, as well as in the proliferation and differentiation of oligodendroglial precursors, improving the preservation of myelin and axonal integrity. Therefore, our results support a treatment with the safe VP3.15 as an integrative therapeutic strategy for the treatment of PPMS.
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spelling pubmed-96946902022-11-26 The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis Benítez-Fernández, Rocio Gil, Carmen Guaza, Carmen Mestre, Leyre Martínez, Ana Int J Mol Sci Article Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while protecting and repairing the nervous system are urgent. That is of utmost importance for the primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS, characterized by worsening neurological function from the onset of symptoms. In this sense, inhibitors of glycogen synthase kinase 3β (GSK3β) and phosphodiesterase 7 (PDE7) have recently shown great therapeutic potential for the treatment of demyelinating diseases. Here we investigated a dual inhibitor of these two targets, the small molecule VP3.15, in a preclinical model, which resembles primary-progressive MS (PPMS), the Theiler’s mouse encephalomyelitis virus-induced demyelinated disease (TMEV-IDD). In our study, VP3.15 ameliorates the disease course improving motor deficits of infected mice. Chronic treatment with VP3.15 also showed significant efficacy in the immunomodulation process, as well as in the proliferation and differentiation of oligodendroglial precursors, improving the preservation of myelin and axonal integrity. Therefore, our results support a treatment with the safe VP3.15 as an integrative therapeutic strategy for the treatment of PPMS. MDPI 2022-11-19 /pmc/articles/PMC9694690/ /pubmed/36430856 http://dx.doi.org/10.3390/ijms232214378 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Benítez-Fernández, Rocio
Gil, Carmen
Guaza, Carmen
Mestre, Leyre
Martínez, Ana
The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis
title The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis
title_full The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis
title_fullStr The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis
title_full_unstemmed The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis
title_short The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis
title_sort dual pde7-gsk3β inhibitor, vp3.15, as neuroprotective disease-modifying treatment in a model of primary progressive multiple sclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9694690/
https://www.ncbi.nlm.nih.gov/pubmed/36430856
http://dx.doi.org/10.3390/ijms232214378
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