2.2.1. Fingolimod

As noted above, the therapeutic e ffects of FGM appear to result at least in part from control of lymphocyte tra fficking via down-regulation of lymphocyte S1PR-1 (Figure 4) [68,69]. There is also growing evidence from preclinical studies, that some of FGM's therapeutic e ffects may be independent of lymphocyte sequestration in peripheral lymphoid organs [38,69]. FGM readily crosses the BBB, potentially enabling its subsequent modulation of S1PRs [35,69,70].

There is up-regulation of S1PR-1- and S1PR-3-expressing astrocytes [71] during active inflammation, and there is growing evidence that astrocytes expressing S1PR-1 may be a primary FGM therapeutic target in the CNS [72]. Consistent with this view has been the demonstration of diminished therapeutic benefit of FGM in EAE in the absence of S1PR-1 expression on astrocytes in genetic knock down mice [38].

Fingolimod, which causes the internalization and destruction of astrocytic S1PR-1 [38] also enhances remyelination in a number of di fferent in vitro models and in EAE mice [40,45,73–75], prevents OLG death, reduces the number of reactive astrocytes and reduces the number of reactive MGL. These beneficial e ffects are mimicked by the selective S1PR-1 antagonist CYM5442, which also prevents the up-regulation of S1PR-1 on astrocytes [45]. As further evidence of the importance of the astrocyte S1PR-1 receptor, the S1PR-1 gene is primarily expressed in astrocytes, its coupled-G-protein-regulated pathway promotes astrocyte proliferation, and its selective blockade inhibits astrogliosis, potentially reducing OLG death and demyelination. These results are supporting evidence that at least some of the protective e ffects of FGM are mediated via S1PR-1 negative modulation in the CNS [45]. As further support, deletion of the astrocyte S1PR-1 gene reduces production of the pro-inflammatory cytokines IL-1β, IL-6 and IL-17, reduces demyelination, and eliminates any additive benefit of CNS protection by FGM treatment [38].
