Our results clearly demonstrate that inhibition of S100B–RAGE interaction may have a dual role in both the protection of myelin sheath upon lysophosphatidylcholine (LPC)-induced demyelination, as well as in the resolution of the inflammatory milieu favoring a faster remyelination and preservation of neuronal structures, further supporting a critical role of this axis in MS pathogenesis. This evidence concerns the gene AGER and myeloid sarcoma.