Experimental Neurology Vol 279, May 2016, P243-260
The multiple sclerosis drug fingolimod (FTY720) stimulates neuronal gene expression, axonal growth and regeneration
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, G12/13 G-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.
Figure 1: (A) Outline of the facial nerve lesion model with the facial nerve represented as a solid blue line (at the start), dashed line (degenerating after its cut/axotomy) and red line (after injection of the Flurogold [FG] tracer 15 days following cutting). The facial nucleus (the start of the facial nerve in the brainstem) is stained with anti-FG antibodies to visualize the FG tracer. Fingolimod enhanced the number of FG positive motoneurones on the lesioned side (E) compared to sham/DMSO injected animals (D).
What happens when two different roads do not lead to the same place? We see this often in science, where one promising breakthrough is quickly disapproved by the turn of an article in the very same journal. Fingolimod (FTY720) has ridden a rocky road in terms of demonstrating its potential for remyelination (see http://multiple-sclerosis-research.blogspot.com/2015/07/novartis-maybe-now-believes-biogen.html; http://multiple-sclerosis-research.blogspot.com/2011/07/fingolimod-does-not-promote.html). But is it right to ignore new information because it disagrees with the desired results?
Here, the authors provide more basic science evidence supporting a role for fingolimod in nerve repair, specifically neuronal repair. They demonstrate that fingolimod induces expression of neuronal plasticity associated genes c-Fos, c-FosB, Bdnf, Egr1 and Egr2, as well as genes encoding components of the actin cytoskeleton that make up axons. They also provide in vitro evidence that fingolimod stimulates growth cone filopodia extension in primary neurones (i.e. demonstrating a potential for initiating axonal growth in the CNS) and in vivo evidence that it enhances axonal regeneration of an injured facial nerve (peripheral nerve, see Figure 1). So there may be additional beneficial effects to fingolimod than simply sequestration of auto-reactive immune cells in lymph nodes. But like most findings in science, I don’t think contradictory findings in science are senseless in themselves, but a necessary paradox.