Cargando…

Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling

BACKGROUND: The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P(1) receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatm...

Descripción completa

Detalles Bibliográficos
Autores principales: Szepanowski, Fabian, Derksen, Angelika, Steiner, Irina, Meyer zu Hörste, Gerd, Daldrup, Thomas, Hartung, Hans-Peter, Kieseier, Bernd C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901498/
https://www.ncbi.nlm.nih.gov/pubmed/27283020
http://dx.doi.org/10.1186/s12974-016-0612-9
_version_ 1782436817516101632
author Szepanowski, Fabian
Derksen, Angelika
Steiner, Irina
Meyer zu Hörste, Gerd
Daldrup, Thomas
Hartung, Hans-Peter
Kieseier, Bernd C.
author_facet Szepanowski, Fabian
Derksen, Angelika
Steiner, Irina
Meyer zu Hörste, Gerd
Daldrup, Thomas
Hartung, Hans-Peter
Kieseier, Bernd C.
author_sort Szepanowski, Fabian
collection PubMed
description BACKGROUND: The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P(1) receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatment of multiple sclerosis. An emerging body of experimental evidence points to additional direct effects on cells of the central and peripheral nervous system. Furthermore, fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Here we investigated whether modulation of particular signaling aspects of S1P as well as LPA by fingolimod might propagate peripheral nerve regeneration in vivo and independent of its anti-inflammatory potency. METHODS: Sciatic nerve crush was performed in wildtype C57BL/6, in immunodeficient Rag1(−/−) and Foxn1(−/−) mice. Analyses were based on walking track analysis and electrophysiology, histology, and cAMP formation. Quantification of different LPA species was performed by liquid chromatography coupled to tandem mass spectrometry. Furthermore, functional consequences of autotaxin inhibition by the specific inhibitor PF-8380 and the impact of fingolimod on early cytokine release in the injured sciatic nerve were investigated. RESULTS: Clinical and electrophysiological measures indicated an improvement of nerve regeneration under fingolimod treatment that is partly independent of its anti-inflammatory properties. Fingolimod treatment correlated with a significant elevation of axonal cAMP, a crucial factor for axonal outgrowth. Additionally, fingolimod significantly reduced LPA levels in the injured nerve. PF-8380 treatment correlated with improved myelin thickness. Sciatic nerve cytokine levels were not found to be significantly altered by fingolimod treatment. CONCLUSIONS: Our findings provide in vivo evidence for direct effects of fingolimod on cells of the peripheral nervous system that may propagate nerve regeneration via a dual mode of action, differentially affecting axonal outgrowth and myelination by modulating relevant aspects of S1P and LPA signaling.
format Online
Article
Text
id pubmed-4901498
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-49014982016-06-11 Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling Szepanowski, Fabian Derksen, Angelika Steiner, Irina Meyer zu Hörste, Gerd Daldrup, Thomas Hartung, Hans-Peter Kieseier, Bernd C. J Neuroinflammation Research BACKGROUND: The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P(1) receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatment of multiple sclerosis. An emerging body of experimental evidence points to additional direct effects on cells of the central and peripheral nervous system. Furthermore, fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Here we investigated whether modulation of particular signaling aspects of S1P as well as LPA by fingolimod might propagate peripheral nerve regeneration in vivo and independent of its anti-inflammatory potency. METHODS: Sciatic nerve crush was performed in wildtype C57BL/6, in immunodeficient Rag1(−/−) and Foxn1(−/−) mice. Analyses were based on walking track analysis and electrophysiology, histology, and cAMP formation. Quantification of different LPA species was performed by liquid chromatography coupled to tandem mass spectrometry. Furthermore, functional consequences of autotaxin inhibition by the specific inhibitor PF-8380 and the impact of fingolimod on early cytokine release in the injured sciatic nerve were investigated. RESULTS: Clinical and electrophysiological measures indicated an improvement of nerve regeneration under fingolimod treatment that is partly independent of its anti-inflammatory properties. Fingolimod treatment correlated with a significant elevation of axonal cAMP, a crucial factor for axonal outgrowth. Additionally, fingolimod significantly reduced LPA levels in the injured nerve. PF-8380 treatment correlated with improved myelin thickness. Sciatic nerve cytokine levels were not found to be significantly altered by fingolimod treatment. CONCLUSIONS: Our findings provide in vivo evidence for direct effects of fingolimod on cells of the peripheral nervous system that may propagate nerve regeneration via a dual mode of action, differentially affecting axonal outgrowth and myelination by modulating relevant aspects of S1P and LPA signaling. BioMed Central 2016-06-10 /pmc/articles/PMC4901498/ /pubmed/27283020 http://dx.doi.org/10.1186/s12974-016-0612-9 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Szepanowski, Fabian
Derksen, Angelika
Steiner, Irina
Meyer zu Hörste, Gerd
Daldrup, Thomas
Hartung, Hans-Peter
Kieseier, Bernd C.
Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
title Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
title_full Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
title_fullStr Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
title_full_unstemmed Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
title_short Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
title_sort fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901498/
https://www.ncbi.nlm.nih.gov/pubmed/27283020
http://dx.doi.org/10.1186/s12974-016-0612-9
work_keys_str_mv AT szepanowskifabian fingolimodpromotesperipheralnerveregenerationviamodulationoflysophospholipidsignaling
AT derksenangelika fingolimodpromotesperipheralnerveregenerationviamodulationoflysophospholipidsignaling
AT steineririna fingolimodpromotesperipheralnerveregenerationviamodulationoflysophospholipidsignaling
AT meyerzuhorstegerd fingolimodpromotesperipheralnerveregenerationviamodulationoflysophospholipidsignaling
AT daldrupthomas fingolimodpromotesperipheralnerveregenerationviamodulationoflysophospholipidsignaling
AT hartunghanspeter fingolimodpromotesperipheralnerveregenerationviamodulationoflysophospholipidsignaling
AT kieseierberndc fingolimodpromotesperipheralnerveregenerationviamodulationoflysophospholipidsignaling