Fingolimod is a sphingosine-1-phophaste receptor (S1PR) modulator. There are five S1PR. The immune modulating effect is mediated by S1P1R. Siponimod is an S1P1R and S1P5R selective modulator. Fingo also binds to S1P3R (this causes some of the heart related issues) and S1P4R in addition to S1P1R and S1P5R. S1P5R is found on glial cells and it has been suggested that repair and protection can occur via this receptor. However if this were true, you may have thought that fingo would work in progressive MS. Our work in progressive EAE suggested otherwise and this was subsequently shown in MS.
Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D.Mult Scler. 2011;17(8):939-48.
However, people are still hunting to see if fingo aguments remyelination. However if we look in a mouse remyelination model there was no effect and perhaps this lack of neuroprotection is because it doesn’t bind to S1P2. If this is important siponimod and ozanimod(S1P1R & S1P5R) will not fair much better.
Perhaps we have to start looking away from monotherapies and look at add-ons to start tackling the effects of progression
Fingolimod downregulates brain sphingosine-1-phosphate receptor 1 levels but does not promote remyelination or neuroprotection in the cuprizone model. Nystad AE, Lereim RR, Wergeland S, Oveland E, Myhr KM, Bø L, Torkildsen Ø. J Neuroimmunol. 2019 Oct 31;339:577091. doi: 10.1016/j.jneuroim.2019.577091. [Epub ahead of print]
Fingolimod is used to treat patients with relapsing-remitting multiple sclerosis; it crosses the blood-brain barrier and modulates sphingosine-1-phosphate receptors (S1PRs). Oligodendrocytes, astrocytes, microglia, and neuronal cells express S1PRs, and fingolimod could potentially improve remyelination and be neuroprotective. We used the cuprizone animal model, histo-, immunohistochemistry, and quantitative proteomics to study the effect of fingolimod on remyelination and axonal damage. Fingolimod was functionally active during remyelination by downregulating S1PR1 brain levels, and fingolimod-treated mice had more oligodendrocytes in the secondary motor cortex after three weeks of remyelination. However, there were no differences in remyelination or axonal damage compared to placebo. Thus, fingolimod does not seem to directly promote remyelination or protect against axonal injury or loss when given after cuprizone-induced demyelination.
Sphingosine 1-phosphate but not Fingolimod protects neurons against excitotoxic cell death by inducing neurotrophic gene expression in astrocytes. Tran C, Heng B, Teo JD, Humphrey SJ, Qi Y, Couttas TA, Stefen H, Brettle M, Fath T, Guillemin GJ, Don AS.J Neurochem. 2019 Nov 19. doi: 10.1111/jnc.14917. [Epub ahead of print]. Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through a family of five G-protein coupled receptors, S1PR1-S1PR5, to regulate cell physiology. The multiple sclerosis drug Fingolimod (FTY720) is a potent S1P receptor agonist that causes peripheral lymphopenia. Recent research has demonstrated direct neuroprotective properties of FTY720 in several neurodegenerative paradigms, however neuroprotective properties of the native ligand S1P have not been established. We aimed to establish the significance of neurotrophic factor up-regulation by S1P for neuroprotection, comparing S1P with FTY720. S1P induced brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), platelet-derived growth factor B (PDGFB) and heparin-binding EGF-like growth factor (HBEGF) gene expression in primary human and murine astrocytes, but not in neurons, and to a much greater extent than FTY720. Accordingly, S1P but not FTY720 protected cultured neurons against excitotoxic cell death in a primary murine neuron-glia co-culture model, and a neutralizing antibody to LIF blocked this S1P-mediated neuroprotection. Antagonists of S1PR1 and S1PR2 both inhibited S1P-mediated neurotrophic gene induction in human astrocytes, indicating that simultaneous activation of both receptors is required. S1PR2 signaling was transduced through Gα13 and the small GTPase Rho, and was necessary for up-regulation and activation of the transcription factors FOS and JUN, which regulate LIF, BDNF and HBEGF transcription. In summary, we show that S1P protects hippocampal neurons against excitotoxic cell death through up-regulation of neurotrophic gene expression, particularly LIF, in astrocytes. This up-regulation requires both S1PR1 and S1PR2 signaling. FTY720 does not activate S1PR2, explaining its relative inefficacy compared to S1P.