Friday, 8 December 2017

Fingolimod: does it help with upper limb function?

ProfG G has been been saying that we should #Thinkhand and target hand function for outcomes in clinical trials. This idea may be supported by studies with ocrelizumab and natalizumab but there are a couple of exceptions.

This is the case with the Sphingosine-1-phosphate receptor modulators. Fingolimod and Siponimod have not impacted on the nine hole peg test. Is this because the trials were not for long enough or is it because it is doing something different?

Fingolimod acts on SP1P1, S1P3, S1P4 and S1P5 receptors and it has been intimated that the effect on immune cells is via S1P1 receptors. However there are claims that glia affects are via S1P5 receptors although this has not really been substantiated.

Does it promote remyelination according to new data?

Kim S, Bielawski J, Yang H, Kong Y, Zhou B, Li J. Functional antagonism of sphingosine-1-phosphate receptor 1 prevents cuprizone-induced demyelination.Glia. 2017 Nov 29. doi: 10.1002/glia.23272. [Epub ahead of print]. Recent evidence suggests that the oral drug Fingolimod (FTY720) for relapsing-remitting multiple sclerosis (MS) may act directly on the central nervous system (CNS) and modulate disease pathogenesis and progression in experimental models of MS. However, the specific subtype of sphingosine-1-phosphate (S1P) receptors that mediates the effect of FTY720 on the CNS cells has not been fully elucidated. Here, we report that S1P receptor 1 (S1PR1) is elevated in reactive astrocytes in an autoimmunity independent mouse model of MS and that selective S1PR1 modulation is sufficient to ameliorate the loss of oligodendrocytes and demyelination. The non-selective S1PR modulator, FTY720, or a short-lived S1PR1-specific modulator, CYM5442, was administered daily to mice while on cuprizone diet. Both FTY720- and CYM5422-treated mice displayed a significant reduction in oligodendrocyte apoptosis and astrocyte and microglial activation in comparison to vehicle-treated groups, which was associated with decreased production of proinflammatory mediators and down-regulation of astrocytic S1PR1 protein. Interestingly, S1PR1 modulation during the early phase of cuprizone intoxication was required to suppress oligodendrocyte death and consequent demyelination as drug treatment from 10 days after the initiation of cuprizone feeding was no longer effective. CYM5442 treatment during the brief cuprizone exposure significantly prevented Il-1β, Il-6, Cxcl10, and Cxcl3 induction, resulting in suppression of subsequent reactive gliosis and demyelination. Our study identifies functional antagonism of S1PR1 as a major mechanism for the protective effect of FTY720 in the cuprizone model and suggests pathogenic contributions of astrocyte S1PR1 signaling in primary demyelination and its potential as a therapeutic target for CNS inflammation.



Alme MN, Nystad AE, Bø L, Myhr KM, Vedeler CA, Wergeland S, Torkildsen Ø. J Neuroimmunol. 2015 Aug 15;285:180-6.

The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination. Slowik A, Schmidt T, Beyer C, Amor S, Clarner T, Kipp M.Br J Pharmacol. 2015 Jan;172(1):80-92.


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. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this compound alleviated ongoing axonal damage

Sphingosine 1-phosphate receptor modulator fingolimod (FTY720) does not promote remyelination in vivo.Hu Y, Lee X, Ji B, Guckian K, Apicco D, Pepinsky RB, Miller RH, Mi S. Mol Cell Neurosci. 2011 Sep;48(1):72-81

Does it affect synapses?

Some reports says it promotes then so that would not answer the question. 

Will the other spingospine-1-phophaste inhibitors, likewise fail to slow worsening of hand function?

However if they do promote remyelination, Is the influence of these agents on MS enough to say that remyelination is really going to make a big impact?


  1. Fingolimod and Siponimod have not impacted on the nine hole peg test.

    Does that say something/anything about the length-dependent theory?


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