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Fingolimod for the treatment of neurological diseases—state of play and future perspectives

Sphingolipids are a fascinating class of signaling molecules derived from the membrane lipid sphingomyelin. They show abundant expression in the brain. Complex sphingolipids such as glycosphingolipids (gangliosides and cerebrosides) regulate vesicular transport and lysosomal degradation and their dy...

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Autores principales: Brunkhorst, Robert, Vutukuri, Rajkumar, Pfeilschifter, Waltraud
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162362/
https://www.ncbi.nlm.nih.gov/pubmed/25309325
http://dx.doi.org/10.3389/fncel.2014.00283
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author Brunkhorst, Robert
Vutukuri, Rajkumar
Pfeilschifter, Waltraud
author_facet Brunkhorst, Robert
Vutukuri, Rajkumar
Pfeilschifter, Waltraud
author_sort Brunkhorst, Robert
collection PubMed
description Sphingolipids are a fascinating class of signaling molecules derived from the membrane lipid sphingomyelin. They show abundant expression in the brain. Complex sphingolipids such as glycosphingolipids (gangliosides and cerebrosides) regulate vesicular transport and lysosomal degradation and their dysregulation can lead to storage diseases with a neurological phenotype. More recently, simple sphingolipids such ceramide, sphingosine and sphingosine 1-phosphate (S1P) were discovered to signal in response to many extracellular stimuli. Forming an intricate signaling network, the balance of these readily interchangeable mediators is decisive for cell fate under stressful conditions. The immunomodulator fingolimod is the prodrug of an S1P receptor agonist. Following receptor activation, the drug leads to downregulation of the S1P(1) receptor inducing functional antagonism. As the first drug to modulate the sphingolipid signaling pathway, it was marketed in 2010 for the treatment of multiple sclerosis (MS). At that time, immunomodulation was widely accepted as the key mechanism of fingolimod’s efficacy in MS. But given the excellent passage of this lipophilic compound into the brain and its massive brain accumulation as well as the abundant expression of S1P receptors on brain cells, it is conceivable that fingolimod also affects brain cells directly. Indeed, a seminal study showed that the protective effect of fingolimod in experimental autoimmune encephalitis (EAE), a murine MS model, is lost in mice lacking the S1P(1) receptor on astrocytes, arguing for a specific role of astrocytic S1P signaling in MS. In this review, we discuss the role of sphingolipid mediators and their metabolizing enzymes in neurologic diseases and putative therapeutic strategies arising thereof.
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spelling pubmed-41623622014-10-10 Fingolimod for the treatment of neurological diseases—state of play and future perspectives Brunkhorst, Robert Vutukuri, Rajkumar Pfeilschifter, Waltraud Front Cell Neurosci Neuroscience Sphingolipids are a fascinating class of signaling molecules derived from the membrane lipid sphingomyelin. They show abundant expression in the brain. Complex sphingolipids such as glycosphingolipids (gangliosides and cerebrosides) regulate vesicular transport and lysosomal degradation and their dysregulation can lead to storage diseases with a neurological phenotype. More recently, simple sphingolipids such ceramide, sphingosine and sphingosine 1-phosphate (S1P) were discovered to signal in response to many extracellular stimuli. Forming an intricate signaling network, the balance of these readily interchangeable mediators is decisive for cell fate under stressful conditions. The immunomodulator fingolimod is the prodrug of an S1P receptor agonist. Following receptor activation, the drug leads to downregulation of the S1P(1) receptor inducing functional antagonism. As the first drug to modulate the sphingolipid signaling pathway, it was marketed in 2010 for the treatment of multiple sclerosis (MS). At that time, immunomodulation was widely accepted as the key mechanism of fingolimod’s efficacy in MS. But given the excellent passage of this lipophilic compound into the brain and its massive brain accumulation as well as the abundant expression of S1P receptors on brain cells, it is conceivable that fingolimod also affects brain cells directly. Indeed, a seminal study showed that the protective effect of fingolimod in experimental autoimmune encephalitis (EAE), a murine MS model, is lost in mice lacking the S1P(1) receptor on astrocytes, arguing for a specific role of astrocytic S1P signaling in MS. In this review, we discuss the role of sphingolipid mediators and their metabolizing enzymes in neurologic diseases and putative therapeutic strategies arising thereof. Frontiers Media S.A. 2014-09-12 /pmc/articles/PMC4162362/ /pubmed/25309325 http://dx.doi.org/10.3389/fncel.2014.00283 Text en Copyright © 2014 Brunkhorst, Vutukuri and Pfeilschifter. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Brunkhorst, Robert
Vutukuri, Rajkumar
Pfeilschifter, Waltraud
Fingolimod for the treatment of neurological diseases—state of play and future perspectives
title Fingolimod for the treatment of neurological diseases—state of play and future perspectives
title_full Fingolimod for the treatment of neurological diseases—state of play and future perspectives
title_fullStr Fingolimod for the treatment of neurological diseases—state of play and future perspectives
title_full_unstemmed Fingolimod for the treatment of neurological diseases—state of play and future perspectives
title_short Fingolimod for the treatment of neurological diseases—state of play and future perspectives
title_sort fingolimod for the treatment of neurological diseases—state of play and future perspectives
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162362/
https://www.ncbi.nlm.nih.gov/pubmed/25309325
http://dx.doi.org/10.3389/fncel.2014.00283
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