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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Autores: Díaz Lucena, Daniela, Gutierrez Mecinas, María, Moreno, Beatriz, Martínez Sánchez, José Lupicinio, Pifarre, Paula, García, Agustina
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/172838
Acceso en línea:https://hdl.handle.net/2445/172838
Access Level:acceso abierto
Palabra clave:Esclerosi múltiple
Mielina
Multiple sclerosis
Myelin
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spelling Mechanisms Involved in the Remyelinating Effect of Sildenafil Díaz Lucena, Daniela Gutierrez Mecinas, María Moreno, Beatriz Martínez Sánchez, José Lupicinio Pifarre, Paula García, Agustina Esclerosi múltiple Mielina Multiple sclerosis Myelin 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. Springer https://hdl.handle.net/2445/172838
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
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
topic Esclerosi múltiple
Mielina
Multiple sclerosis
Myelin
topic_facet 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
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url https://hdl.handle.net/2445/172838
eu_rights_str_mv openAccess
publisher Springer
institution Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
collection Recercat. Dipósit de la Recerca de Catalunya
reponame_str Recercat. Dipósit de la Recerca de Catalunya
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
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publishDateSort 2018
author_browse Díaz Lucena, Daniela
García, Agustina
Gutierrez Mecinas, María
Martínez Sánchez, José Lupicinio
Moreno, Beatriz
Pifarre, Paula
publisherStr Springer
score 6,924472

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