Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling.
The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P1 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.



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.



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.



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.
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. fabian.szepanowski@uni-duesseldorf.de.
Fabian
F
Szepanowski
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Angelika
A
Derksen
Department of Forensic Toxicology, Institute of Legal Medicine, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Irina
I
Steiner
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.|Evergrande Center for Immunologic Diseases, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Department of Neurology, University of Münster, Münster, Germany.
Gerd
G
Meyer Zu Hörste
Department of Forensic Toxicology, Institute of Legal Medicine, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Thomas
T
Daldrup
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Hans-Peter
HP
Hartung
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Bernd C
BC
Kieseier
D000818:Animals; D001583:Benzoxazoles / Q000627:therapeutic use; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use*; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000187:drug effects*; D009431:Neural Conduction / Q000187:drug effects / Q000235:genetics; D016900:Neurofilament Proteins / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects*
C550725:6-(3-(piperazin-1-yl)propanoyl)benzo(d)oxazol-2(3H)-one; D001583:Benzoxazoles; D016207:Cytokines; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D016900:Neurofilament Proteins; D010879:Piperazines; C090140:Whn protein; C044882:neurofilament protein L; C064658:RAG-1 protein; D000242:Cyclic AMP; D000068876:Fingolimod Hydrochloride
Fingolimod; Lysophosphatidic acid; PF-8380; Peripheral nerve regeneration; Sphingosine-1-phosphate