Remyelination, which occurs subsequent to demyelination, contributes to functional
recovery and is mediated by oligodendrocyte progenitor cells (OPCs) that have differentiated
into myelinating cells. Therapeutics that impact remyelination in the CNS could be
critical determinants of long-term functional outcome in multiple sclerosis (MS).
Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory
properties, yet may impact cells within the CNS by crossing the blood-brain barrier.
Previous studies using isolated dissociated cultures indicate that neural cells express
S1P receptors and respond to receptor engagement. Our objective was to assess the
effects of fingolimod on myelin-related processes within a multicellular environment
that maintains physiological cell-cell interactions, using organotypic cerebellar
slice cultures. Fingolimod treatment had no impact on myelin under basal conditions.
Fingolimod treatment subsequent to lysolecithin-induced demyelination enhanced remyelination
and process extension by OPCs and mature oligodendrocytes, while increasing microglia
numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein.
The number of phagocytosing microglia was not increased by fingolimod. Using S1P receptor
specific agonists and antagonists, we determined that fingolimod-induced effects on
remyelination and astrogliosis were mediated primarily through S1P3 and S1P5, whereas
enhanced microgliosis was mediated through S1P1 and S1P5. Taken together, these data
demonstrate that fingolimod modulates multiple neuroglial cell responses, resulting
in enhanced remyelination in organotypic slice cultures that maintain the complex
cellular interactions of the mammalian brain.