Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices.
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.
Miron
Veronique E
VE
Neuroimmunology Unit, McGill University, Montreal Neurological Institute, 3801 University St., Montreal, QC, Canada, H3A 2B4.
Ludwin
Samuel K
SK
Darlington
Peter J
PJ
Jarjour
Andrew A
AA
Soliven
Betty
B
Kennedy
Timothy E
TE
Antel
Jack P
JP
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy*; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008244:Lysophosphatidylcholines / Q000633:toxicity; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000503:physiopathology; D009186:Myelin Sheath / Q000502:physiology*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D046509:Tissue Culture Techniques
D007166:Immunosuppressive Agents; D008244:Lysophosphatidylcholines; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine