Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis

Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-...

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Autores: Navarrete, Carmen, García-Martín, A, Garrido-Rodriguez, Martín, Mestre, Leyre, Feliú, Ana, Guaza, Carmen, Calzado, Marco A., Muñoz, Eduardo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/219645
Acceso en línea:http://hdl.handle.net/10261/219645
Access Level:acceso abierto
Palabra clave:Multiple sclerosis
EHP-101
Transcriptomic
Inflammation
Remyelination
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spelling Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosisNavarrete, CarmenGarcía-Martín, AGarrido-Rodriguez, MartínMestre, LeyreFeliú, AnaGuaza, CarmenCalzado, Marco A.Muñoz, EduardoMultiple sclerosisEHP-101TranscriptomicInflammationRemyelinationMultiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/ Cannabinoid receptor type 2 (PPAR¿/CB2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic, and neurodegenerative diseases. EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord. EHP-101 normalized the expression of several genes associated with oligodendrocyte function such as Teneurin 4 (Tenm4) and Gap junction gamma-3 (Gjc3) that were downregulated in EAE. EHP-101 treatment prevented microglia activation and demyelination in both the spinal cord and the brain. Moreover, EAE was associated with a loss in the expression of Oligodendrocyte transcription factor 2 (Olig2) in the corpus callosum, a marker for oligodendrocyte differentiation, which was restored by EHP-101 treatment. In addition, EHP-101 enhanced the expression of glutathione S-transferase pi (GSTpi), a marker for mature oligodendrocytes in the brain. We also found that a diet containing 0.2% cuprizone for six weeks induced a clear loss of myelin in the brain measured by Cryomyelin staining and Myelin basic protein (MBP) expression. Moreover, EHP-101 also prevented cuprizone induced microglial activation, astrogliosis and reduced axonal damage. Our results provide evidence that EHP- 101 showed potent anti-inflammatory activity, prevented demyelination, and enhanced remyelination. Therefore, EHP-101 represents a promising drug candidate for the potential treatment of different forms of MS.This work was supported by grants SAF2017–87701-R (EM), SAF2016–76449-R (GC) from the Ministry of the Economy and Competition (MINECO) co-financed with the European Union FEDER funds. GC was also supported by the Red Española de Esclerosis Múltiple (REEM: RD16/0015/0021) sponsored by the Fondo de Investigación Sanitaria (FIS) (GC). This work was also partially supported by Emerald Health Pharmaceuticals (San Diego, USA).Academic PressMinisterio de Economía y Competitividad (España)European CommissionRed Española de Esclerosis MúltipleInstituto de Salud Carlos IIIEmerald Health PharmaceuticalsConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/219645reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017–87701-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016–76449-Rhttp://dx.doi.org/10.1016/j.nbd.2020.104994Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2196452026-05-22T06:33:51Z
dc.title.none.fl_str_mv Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis
title Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis
spellingShingle Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis
Navarrete, Carmen
Multiple sclerosis
EHP-101
Transcriptomic
Inflammation
Remyelination
title_short Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis
title_full Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis
title_fullStr Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis
title_full_unstemmed Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis
title_sort Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis
dc.creator.none.fl_str_mv Navarrete, Carmen
García-Martín, A
Garrido-Rodriguez, Martín
Mestre, Leyre
Feliú, Ana
Guaza, Carmen
Calzado, Marco A.
Muñoz, Eduardo
author Navarrete, Carmen
author_facet Navarrete, Carmen
García-Martín, A
Garrido-Rodriguez, Martín
Mestre, Leyre
Feliú, Ana
Guaza, Carmen
Calzado, Marco A.
Muñoz, Eduardo
author_role author
author2 García-Martín, A
Garrido-Rodriguez, Martín
Mestre, Leyre
Feliú, Ana
Guaza, Carmen
Calzado, Marco A.
Muñoz, Eduardo
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
European Commission
Red Española de Esclerosis Múltiple
Instituto de Salud Carlos III
Emerald Health Pharmaceuticals
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Multiple sclerosis
EHP-101
Transcriptomic
Inflammation
Remyelination
topic Multiple sclerosis
EHP-101
Transcriptomic
Inflammation
Remyelination
description Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/ Cannabinoid receptor type 2 (PPAR¿/CB2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic, and neurodegenerative diseases. EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord. EHP-101 normalized the expression of several genes associated with oligodendrocyte function such as Teneurin 4 (Tenm4) and Gap junction gamma-3 (Gjc3) that were downregulated in EAE. EHP-101 treatment prevented microglia activation and demyelination in both the spinal cord and the brain. Moreover, EAE was associated with a loss in the expression of Oligodendrocyte transcription factor 2 (Olig2) in the corpus callosum, a marker for oligodendrocyte differentiation, which was restored by EHP-101 treatment. In addition, EHP-101 enhanced the expression of glutathione S-transferase pi (GSTpi), a marker for mature oligodendrocytes in the brain. We also found that a diet containing 0.2% cuprizone for six weeks induced a clear loss of myelin in the brain measured by Cryomyelin staining and Myelin basic protein (MBP) expression. Moreover, EHP-101 also prevented cuprizone induced microglial activation, astrogliosis and reduced axonal damage. Our results provide evidence that EHP- 101 showed potent anti-inflammatory activity, prevented demyelination, and enhanced remyelination. Therefore, EHP-101 represents a promising drug candidate for the potential treatment of different forms of MS.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/219645
url http://hdl.handle.net/10261/219645
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017–87701-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016–76449-R
http://dx.doi.org/10.1016/j.nbd.2020.104994
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Academic Press
publisher.none.fl_str_mv Academic Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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repository.mail.fl_str_mv
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