Mechanisms Involved in the Remyelinating Effect of Sildenafil

Díaz-Lucena, Daniela; Gutièrrez‐Mecinas, María; Moreno, Beatriz; Martínez-Sánchez, José Lupicinio; Pifarré, Paula; Garcı́a, Agustina

doi:10.1007/s11481-017-9756-3

Cited by 13 publications

(16 citation statements)

References 181 publications

(213 reference statements)

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“…Of note, a recent article described a promoting effect of sildenafil on remyelination (Díaz-Lucena et al., 2018). However, it was suggested that the observed effect is rather related to the modulation of immune cells and not to a direct effect on oligodendroglial cells.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil Inhibits Myelin Expression and Myelination of Oligodendroglial Precursor Cells

et al. 2019

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Phosphodiesterases (PDEs) have previously been implicated in oligodendrocyte maturation and myelination of central nervous system axons. Sildenafil citrate is a phosphodiesterase inhibitor known to block PDE5, which also reduces inflammation in the experimental autoimmune encephalomyelitis demyelinating model. To find out whether this inhibitor might exert beneficial effects on central nervous system myelin repair activities, we investigated to what degree sildenafil modulates differentiation and maturation of cultured primary rat oligodendroglial precursor cells (OPCs). To this end, gene and protein expression of 2′,3′-cyclic-nucleotide 3′-phosphodiesterase, myelin basic protein, and myelin oligodendrocyte glycoprotein, as well as of negative regulators of myelin expression (Hes1, Hes5, Id2, Id4, Rock2, and p57Kip2) were measured in OPCs treated with sildenafil. Moreover, the subcellular distribution of the p57kip2 protein was determined after sildenafil treatment, as this revealed to be an early predictor of the oligodendroglial differentiation capacity. In vitro myelination assays were done to measure the myelination capacity of oligodendrocytes treated with sildenafil. We found that sildenafil significantly diminished myelin gene expression and protein expression. Moreover, sildenafil also increased the expression of Id2 and Id4 negative transcriptional regulators, and the degree of OPCs with cytoplasmic p57kip2 protein localization was reduced, providing evidence that the PDE blocker impaired the differentiation capacity. Finally, sildenafil also interfered with the establishment of internodes as revealed by in vitro myelination assays. We therefore conclude that blocking PDE5 activities exerts a negative impact on intrinsic oligodendroglial differentiation processes.

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Section: Discussionmentioning

confidence: 99%

Sildenafil Inhibits Myelin Expression and Myelination of Oligodendroglial Precursor Cells

et al. 2019

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“…Interestingly, murine studies using EAE have demonstrated that a phenotypic switch of phagocytes from the pro- to the anti-inflammatory phenotype is associated with milder clinical scores (89). Moreover, after focal LPC-induced demyelination, pro-inflammatory phagocytes seem to drive OPC proliferation.…”

Section: Inflammatory Damage Control In Active Ms Lesions By Inhibitimentioning

confidence: 99%

“…Moreover, after focal LPC-induced demyelination, pro-inflammatory phagocytes seem to drive OPC proliferation. However, it is the later switch to the pro-reparative phenotype that is necessary for OPC differentiation into mature myelinating oligodendrocytes that establish functional remyelination (89). Additionally, anti-inflammatory phagocytes are critical contributors in ceasing the inflammatory response and allowing CNS repair (89).…”

Section: Inflammatory Damage Control In Active Ms Lesions By Inhibitimentioning

confidence: 99%

“…However, it is the later switch to the pro-reparative phenotype that is necessary for OPC differentiation into mature myelinating oligodendrocytes that establish functional remyelination (89). Additionally, anti-inflammatory phagocytes are critical contributors in ceasing the inflammatory response and allowing CNS repair (89). Balancing the levels of cAMP and cGMP in phagocytes is considered critical for orchestrating phagocyte polarization and organizing phagocytosis (90).…”

Section: Inflammatory Damage Control In Active Ms Lesions By Inhibitimentioning

confidence: 99%

“…Sildenafil treatment (10 mg/kg, daily s.c injected) improved clinical scores in EAE mice and increased the expression of Ym-1, a canonical anti-inflammatory macrophage marker in the SC of these mice. In addition, PDE5 inhibition promoted phagocytosis of myelin debris (89). Therefore, by inhibiting cAMP-specific PDEs, this pro-inflammatory response can be diminished and disease progression can be halted.…”

Section: Inflammatory Damage Control In Active Ms Lesions By Inhibitimentioning

confidence: 99%

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Targeting Phosphodiesterases—Towards a Tailor-Made Approach in Multiple Sclerosis Treatment

et al. 2019

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Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) characterized by heterogeneous clinical symptoms including gradual muscle weakness, fatigue, and cognitive impairment. The disease course of MS can be classified into a relapsing-remitting (RR) phase defined by periods of neurological disabilities, and a progressive phase where neurological decline is persistent. Pathologically, MS is defined by a destructive immunological and neuro-degenerative interplay. Current treatments largely target the inflammatory processes and slow disease progression at best. Therefore, there is an urgent need to develop next-generation therapeutic strategies that target both neuroinflammatory and degenerative processes. It has been shown that elevating second messengers (cAMP and cGMP) is important for controlling inflammatory damage and inducing CNS repair. Phosphodiesterases (PDEs) have been studied extensively in a wide range of disorders as they breakdown these second messengers, rendering them crucial regulators. In this review, we provide an overview of the role of PDE inhibition in limiting pathological inflammation and stimulating regenerative processes in MS.

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Evaluation of Myelin Phagocytosis by Microglia/Macrophages in Nervous Tissue Using Flow Cytometry

et al. 2021

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Determination of microglial phagocytosis of myelin has acquired importance in the study of demyelinating diseases. One strategy to determine microglial phagocytosis capacity consists of assaying microglia with fluorescently labeled myelin; however, most approaches are performed in cell culture, where microglia usually show important phenotypic differences compared with in vivo conditions. In this article we describe an adapted flow cytometry protocol to assay myelin phagocytosis by microglia obtained directly from in vivo tissue of the central nervous system. Key steps for a first analysis of phagocytic microglia are provided. Additionally, we describe how to fluorescently label myelin using a pH‐sensitive tag, pHrodo™ Green STP Ester. © 2021 Wiley Periodicals LLC. Basic Protocol: Assay for determination of myelin phagocytosis by microglia/macrophages using flow cytometry Support Protocol 1: Conjugation of isolated and purified myelin with pHrodo Green STP Ester Support Protocol 2: Quantification of phagocytic cell number by flow cytometry

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Mechanisms Involved in the Remyelinating Effect of Sildenafil

Cited by 13 publications

References 181 publications

Sildenafil Inhibits Myelin Expression and Myelination of Oligodendroglial Precursor Cells

Sildenafil Inhibits Myelin Expression and Myelination of Oligodendroglial Precursor Cells

Targeting Phosphodiesterases—Towards a Tailor-Made Approach in Multiple Sclerosis Treatment

Evaluation of Myelin Phagocytosis by Microglia/Macrophages in Nervous Tissue Using Flow Cytometry

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