title: The multiple sclerosis drug fingolimod (FTY720) stimulates neuronal gene expression, axonal growth and regeneration.
abstract: Fingolimod (FTY720) is a new generation oral treatment for multiple sclerosis (MS). So far, FTY720 was mainly considered to target trafficking of immune cells but not brain cells such as neurons. Herein, we analyzed FTY720's potential to directly alter neuronal function. In CNS neurons, we identified a FTY720 governed gene expression response. FTY720 upregulated immediate early genes (IEGs) encoding for neuronal activity associated transcription factors such as c-Fos, FosB, Egr1 and Egr2 and induced actin cytoskeleton associated genes (actin isoforms, tropomyosin, calponin). Stimulation of primary neurons with FTY720 enhanced neurite growth and altered growth cone morphology. In accordance, FTY720 enhanced axon regeneration in mice upon facial nerve axotomy. We identified components of a FTY720 engaged signaling cascade including S1P receptors, G12/13G-proteins, RhoA-GTPases and the transcription factors SRF/MRTF. In summary, we uncovered a broader cellular and therapeutic operation mode of FTY720, suggesting beneficial FTY720 effects also on CNS neurons during MS therapy and for treatment of other neurodegenerative diseases requiring neuroprotective and neurorestorative processes.
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Anastasiadou
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Electronic address: bernd.knoell@uni-ulm.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Knöll
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000187:drug effects*; D019771:Axotomy; D002478:Cells, Cultured; D005154:Facial Nerve / Q000187:drug effects / Q000254:growth & development; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects; D020439:Growth Cones / Q000187:drug effects / Q000648:ultrastructure; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009416:Nerve Regeneration / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000199:Actins; D007166:Immunosuppressive Agents; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000068876:Fingolimod Hydrochloride
keywords: Axon regeneration; FTY720; Fingolimod; Growth cone; IEG; Multiple sclerosis; Neurite growth; Neurodegeneration; SRF; Sphingosine; c-Fos