2.2.2. Siponimod

Siponimod is a selective modulator of S1PR-1 and S1PR-5 [76,77], and was originally synthesized to reduce cardiovascular e ffects by eliminating S1PR-3 a ffinity [78,79]. Its structure favors avid penetration of the BBB. It has a short T1/2 elimination, and lymphocyte counts may return to baseline within 48 h of the last dose (see Table 2) [78]. Recent studies in both human and rodent astrocytes have demonstrated that SPM modulates cellular pro-survival pathways [80–82], primarily via S1PR-1 [82]. SPM also demonstrates anti-inflammatory e ffects, reducing phosphatidyl choline, TNF α and IL-17-induced IL-6 production by via S1PR-1 modulation. In an in-situ injected curpizone mouse model, SPM treatment reduces myelin breakdown-associated proteins, decreases the number of damaged axons, decreases OLG loss, increases the number of myelinated axons, and reduces MPG and MGL infiltration [83]. In studies of EAE-induced excitotoxic synaptic degeneration, SPM treatment preserves gabaergic neurons in the striatum, and reduces microgliosis, even in the absence of pro-inflammatory lymphocyte affects. These results have been replicated in brain slices, further supporting a direct SPM a ffect upon the CNS. It has been hypothesized that SPM, via its actions on S1PR-1, reduces MGL activation, which in turn reduces pro-inflammatory lymphocyte recruitment into the CNS [83]. Lastly, since SPM is also a modulator of S1PR-5, preservation of OLGs and myelinated axons in demyelination models following its use is not unexpected. Although, to our knowledge, not ye<sup>t</sup> reported, SPM may also preserve BBB function via S1PR-5 modulation.


**Table 2.** Pharmacokinetics and pharmacodynamics of the S1PR antagonists.

\* Increased by 50% in patients with moderate to severe heart disease, \*\* CC112273 the major ozanimod active metabolite, \*\*\* 90% recovery to baseline lymphocyte count with 3 months.
