Mechanisms Involved in the Remyelinating Effect of Sildenafil

Remyelination occurs in demyelinated lesions in multiple sclerosis (MS) and pharmacological treatments that enhance this process will critically impact the long term functional outcome in the disease. Sildenafil, a cyclic GMP (cGMP)-specific phosphodiesterase 5 inhibitor (PDE5-I), is an oral vasodil...

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Detalhes bibliográficos
Autores: Díaz Lucena, Daniela, Gutierrez Mecinas, María, Moreno, Beatriz, Martínez Sánchez, José Lupicinio, Pifarre, Paula, García, Agustina
Tipo de documento: artigo
Estado:Versión aceptada para publicación
Data de publicação:2018
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/172838
Acesso em linha:https://hdl.handle.net/2445/172838
Access Level:Acceso aberto
Palavra-chave:Esclerosi múltiple
Mielina
Multiple sclerosis
Myelin
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spelling Mechanisms Involved in the Remyelinating Effect of SildenafilDíaz Lucena, DanielaGutierrez Mecinas, MaríaMoreno, BeatrizMartínez Sánchez, José LupicinioPifarre, PaulaGarcía, AgustinaEsclerosi múltipleMielinaMultiple sclerosisMyelinRemyelination occurs in demyelinated lesions in multiple sclerosis (MS) and pharmacological treatments that enhance this process will critically impact the long term functional outcome in the disease. Sildenafil, a cyclic GMP (cGMP)-specific phosphodiesterase 5 inhibitor (PDE5-I), is an oral vasodilator drug extensively used in humans for treatment of erectile dysfunction and pulmonary arterial hypertension. PDE5 is expressed in central nervous system (CNS) neuronal and glial populations and in endothelial cells and numerous studies in rodent models of neurological disease have evidenced the neuroprotective potential of PDE5-Is. Using myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) as a MS model, we previously showed that daily administration of sildenafil starting at peak disease rapidly ameliorates clinical symptoms while administration at symptoms onset prevents disease progression. These beneficial effects of the drug involved down-regulation of adaptive and innate immune responses, protection of axons and oligodendrocytes (OLs) and promotion of remyelination. In this work we have investigated mechanisms involved in the remyelinating effect of sildenafil. Using demyelinated organotypic cerebellar slice cultures we demonstrate that sildenafil stimulates remyelination by direct effects on CNS cells in a nitric oxide (NO)-cGMP-protein kinase G (PKG)-dependent manner. We also show that sildenafil treatment enhances OL maturation and induces expression of the promyelinating factor ciliary neurotrophic factor (CNTF) in spinal cord of EAE mice and in cerebellar slice cultures. Furthermore, we demonstrate that sildenafil promotes a M2 phenotype in bone marrow derived macrophages (BMDM) and increases myelin phagocytosis in these cells and in M2 microglia/macrophages in the spinal cord of EAE mice. Taken together these data indicate that promotion of OL maturation directly or through induction of growth factor expression, regulation of microglia/macrophage inflammatory phenotype and clearance of myelin debris may be relevant mechanisms involved in sildenafil enhancement of remyelination in demyelinated tissue and further support the contention that this well tolerated drug could be useful for ameliorating MS pathology.Springer2020202020182020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion43 p.application/pdfhttps://hdl.handle.net/2445/172838Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1007/s11481-017-9756-3Journal of Neuroimmune Pharmacology, 2018, vol. 13, num. 1, p. 6-23https://doi.org/10.1007/s11481-017-9756-3(c) Springer, 2018info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1728382026-05-29T05:05:01Z
dc.title.none.fl_str_mv Mechanisms Involved in the Remyelinating Effect of Sildenafil
title Mechanisms Involved in the Remyelinating Effect of Sildenafil
spellingShingle Mechanisms Involved in the Remyelinating Effect of Sildenafil
Díaz Lucena, Daniela
Esclerosi múltiple
Mielina
Multiple sclerosis
Myelin
title_short Mechanisms Involved in the Remyelinating Effect of Sildenafil
title_full Mechanisms Involved in the Remyelinating Effect of Sildenafil
title_fullStr Mechanisms Involved in the Remyelinating Effect of Sildenafil
title_full_unstemmed Mechanisms Involved in the Remyelinating Effect of Sildenafil
title_sort Mechanisms Involved in the Remyelinating Effect of Sildenafil
dc.creator.none.fl_str_mv Díaz Lucena, Daniela
Gutierrez Mecinas, María
Moreno, Beatriz
Martínez Sánchez, José Lupicinio
Pifarre, Paula
García, Agustina
author Díaz Lucena, Daniela
author_facet Díaz Lucena, Daniela
Gutierrez Mecinas, María
Moreno, Beatriz
Martínez Sánchez, José Lupicinio
Pifarre, Paula
García, Agustina
author_role author
author2 Gutierrez Mecinas, María
Moreno, Beatriz
Martínez Sánchez, José Lupicinio
Pifarre, Paula
García, Agustina
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Esclerosi múltiple
Mielina
Multiple sclerosis
Myelin
topic Esclerosi múltiple
Mielina
Multiple sclerosis
Myelin
description Remyelination occurs in demyelinated lesions in multiple sclerosis (MS) and pharmacological treatments that enhance this process will critically impact the long term functional outcome in the disease. Sildenafil, a cyclic GMP (cGMP)-specific phosphodiesterase 5 inhibitor (PDE5-I), is an oral vasodilator drug extensively used in humans for treatment of erectile dysfunction and pulmonary arterial hypertension. PDE5 is expressed in central nervous system (CNS) neuronal and glial populations and in endothelial cells and numerous studies in rodent models of neurological disease have evidenced the neuroprotective potential of PDE5-Is. Using myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) as a MS model, we previously showed that daily administration of sildenafil starting at peak disease rapidly ameliorates clinical symptoms while administration at symptoms onset prevents disease progression. These beneficial effects of the drug involved down-regulation of adaptive and innate immune responses, protection of axons and oligodendrocytes (OLs) and promotion of remyelination. In this work we have investigated mechanisms involved in the remyelinating effect of sildenafil. Using demyelinated organotypic cerebellar slice cultures we demonstrate that sildenafil stimulates remyelination by direct effects on CNS cells in a nitric oxide (NO)-cGMP-protein kinase G (PKG)-dependent manner. We also show that sildenafil treatment enhances OL maturation and induces expression of the promyelinating factor ciliary neurotrophic factor (CNTF) in spinal cord of EAE mice and in cerebellar slice cultures. Furthermore, we demonstrate that sildenafil promotes a M2 phenotype in bone marrow derived macrophages (BMDM) and increases myelin phagocytosis in these cells and in M2 microglia/macrophages in the spinal cord of EAE mice. Taken together these data indicate that promotion of OL maturation directly or through induction of growth factor expression, regulation of microglia/macrophage inflammatory phenotype and clearance of myelin debris may be relevant mechanisms involved in sildenafil enhancement of remyelination in demyelinated tissue and further support the contention that this well tolerated drug could be useful for ameliorating MS pathology.
publishDate 2018
dc.date.none.fl_str_mv 2018
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/172838
url https://hdl.handle.net/2445/172838
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1007/s11481-017-9756-3
Journal of Neuroimmune Pharmacology, 2018, vol. 13, num. 1, p. 6-23
https://doi.org/10.1007/s11481-017-9756-3
dc.rights.none.fl_str_mv (c) Springer, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Springer, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 43 p.
application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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