Slowik A, Schmidt T, Beyer C, Amor S, Clarner T, Kipp M. FTY720 is neuroprotective after cuprizone-induced central nervous system demyelination. Br J Pharmacol. 2014. doi: 10.1111/bph.12938. [Epub ahead of print]
BACKGROUND: The sphingosine 1-phosphate (S1P) receptor modulator is an approved treatment of relapsing multiple sclerosis (MS) because of its anti-inflammatory effect to retain lymphocytes within the lymph nodes. Here, we evaluated the potential of FTY720 (fingolimod; Gilenya™, Novartis Pharma AG) to activate pro-myelinating pathways within the brain to encourage remyelination and neuroprotection.
EXPERIMENTAL: APPROACH: In this study, we used the cuprizone model and tested pro-myelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination.
KEY RESULTS: The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute but impaired after chronic demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Gliosis parameters (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein (APP)-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this drug alleviates ongoing axonal damage.
CONCLUSIONS: We show that even during endogenous remyelination, axonal degeneration continues to progress at a low level, accumulating over time, and that this continuous neurodegenerative process is ameliorated by FTY720 treatment. This study demonstrates that FTY720 preserves central nervous system integrity by direct interaction with brain resident cells, the actions of which are still to be defined.
Gilenya is a sphingosine-1-phosphate receptor (S1PR) modulator of which there are a number of variants. S1PR one mediates the immune effects and blocks white blood cells from creeping out of the lymph glands. S1PR5 is found on glial cells in the brain, where Gilenya can concentrate. It has been suggested that Gilenya may be promyelinating and help remyelination. We have published some data indicating that this drug can upregulate myelin genes and this study suggests it can have some effect a helping remyelination after a recent demyelinating event....This however contrasts with a competing companies data that it does nothing for remyelination. However, in established long term demyelination it did not support remyelination in this study either. So further tempering this view that repair is promoted. However, what was noted is that demyelinated axons can die and this is seen by a breakage of the axon. When this occurs a protein in the nerve that shuttles down the nerve ouses out of the cut axon and makes a bleb. There were less blebs suggesting that Gilenja can save nerves. This would therefore be good news for the primary progressive trial that is essentially complete......The investors will be told the results in one of two months time. Fingers crossed for good news.