S1P2 receptor as a target for remyelination

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People have desperately being trying to show that fingolimod promotes remyelination and it has been have notably suggested that it can target glial cells via sphingosine -1-phosphate 5 receptor (S1P-5) adding to the effects on modulation of S1P1 to blcok lymphocyte migration.


Fingolimod blocks activity of S1P1, S1P3, S1P4 and S1P5, is the missing activity on S1P2 a probablem…


Maybe so.



                                          S1PR2 receptor expression from http://www.brainseq2


Seyedsadr MS, Weinmann O, Amorim A, Ineichen BV, Egger M, Mirnajafi-Zadeh J, Becher B, Javan M, Schwab ME. Inactivation of sphingosine-1-phosphate receptor 2 (S1PR2) decreases demyelination and enhances remyelination in animal models of multiple sclerosis. Neurobiol Dis. 2018 Nov 20. pii: S0969-9961(18)30749-6.


Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) in which multiple sites of blood-brain barrier (BBB) disruption, focal inflammation, demyelination and tissue destruction are the hallmarks. Here we show that sphingosine-1-phosphate receptor 2 (S1PR2) has a negative role in myelin repair as well as an important role in demyelination by modulating BBB permeability. In lysolecithin-induced demyelination of adult mouse spinal cord, S1PR2 inactivation by either the pharmacological inhibitor JTE-013 or S1PR2 gene knockout led to enhanced myelin repair as determined by higher numbers of differentiated oligodendrocytes and increased numbers of remyelinated axons at the lesion sites. S1PR2 inactivation in lysolecithin-induced demyelination of the optic chiasm, enhanced oligodendrogenesis and improved the behavioral outcome in an optokinetic reflex test. In order to see the effect of S1PR2 inactivation on demyelination, experimental autoimmune encephalitis (EAE) was induced by MOG-peptide. S1PR2 inhibition or knockout decreased the extent of demyelinated areas as well as the clinical disability in this EAE model. Both toxin induced and EAE models showed decreased BBB leakage and reduced numbers of Iba1+ macrophages following S1PR2 inactivation. Our results suggest that S1PR2 activity impairs remyelination and also enhances BBB leakage and demyelination. The former effect could be mediated by Nogo-A, as antagonism of this factor enhances remyelination and S1PR2 can act as a Nogo-A receptor.


So if we look at the -imods they target S1P1 and S1P5 not S1P2. As you can see it is highly expressed by oligoderocyte precusos cells not oligodendrocytes. This study suggests it promotes remyelination, interesting.


Unfortunately, before we get carried away, as with all the other remyelination agents, they have targets in other cell types besides oligodendrocytes that could cause problems in the long-run from long-term therapy, blockage of S1P2 in animal has been associated with increase angiogenesis (blood vessel formation). This could be bad news as it could promote tumours and when we look at S1P2 knockmice they have an occurance of B cell cancers. Therefore, we have to see where this will go.

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