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.

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…Like numerous cell surface receptor agonists, FTY720P can lead to S1PR internalization, effectively modulating their protein level at the cell surface. However, FTY720 / FTY720P can exert a number of other effects including changes in neuronal gene expression [38], as demonstrated by a previous study on a rat AD model induced by single Aβ injection [55]. In our hands, the long-term presence of AβPP (V717I) has notably modified the cortical responses to the treatment with FTY720.…”

“…The complex interactions of sphingolipids with nuclear gene regulation suggest close links between these pathways, but detailed understanding is missing. The ability of the sphingosine mimetic drug FTY720/fingolimod to modulate gene expression in neurons and astrocytes [38,39] is probably due in large part to the links observed between S1P receptor signaling and the activities of crucial transcription factors including NF-κB, Yin-Yang-1, or Notch [71][72][73][74][75]. However, the inhibition of class I HDACs by FTY720 / FTY720P must also be considered a potential mechanism [41,42].…”

“…FTY720 becomes phosphorylated in the tissue and becomes an S1P analogue, gaining the ability to bind S1PRs (with the disputed exception of S1PR2 [21]), activating them and exerting other effects typical for S1P, such as receptor internalization. FTY720 is able to induce a gene expression program in neurons that modifies their phenotype and potentially might mitigate the loss in connectivity observed in the course of neurodegenerative disorders [38]. FTY720 also causes expression and secretion of a set of neurotrophic factors by astrocytes [39].…”

Fingolimod‐improved axonal and myelin integrity of white matter tracts associated with multiple sclerosis‐related functional impairments

“…Other studies demonstrated a neuroregenerative effect as well as a neuroprotective effect on synapses of murine MS models after fingolimod treatment . The drug elicits a neuronal gene response, modulating neurite growth, and axonal regeneration …”

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

“…For cortical tissue (Figure M), the ΔΔCt method was applied to provide the fold change of mRNA level as follows: 2 −(ΔCt TBI ipsi − ΔCt sham ipsi) . Primer sequences were reported earlier or can be provided upon request …”