Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model.
Fingolimod (FTY720) is a sphingosine 1-phosphate (S1P) receptor modulator that regulates lymphocyte trafficking and exerts pleiotropic actions on oligodendrocytes (OLGs) and other neural cells. The purpose of this study was to investigate the role of S1P receptors in a non-T-cell model of demyelination, the cuprizone (cupr) model in C57BL/6 mice. Treatment with FTY720 (1 mg/kg) led to attenuated injury to OLGs, myelin, and axons in the corpus callosum (percentage of myelinated fibers was 44.7% in cupr-water and 63% in cupr-FTY720). Reactive astrogliosis and microgliosis were ameliorated when FTY720 was given from d 1, but astrogliosis was augmented when FTY720 was given from wk 4-9. FTY720 did not promote remyelination in this model. The protective effect of FTY720 was associated with decreased interleukin-1β and CCL2 transcripts in the corpus callosum, as well as altered S1P1 expression. Targeted deletion of S1P1 in OLG lineage cells did not lead to obvious clinical phenotype, but resulted in subtle abnormalities in myelin and an increased susceptibility to cupr-induced demyelination. We conclude that S1P receptors expressed by neuroglia are involved in regulating the response to injury, and CNS effects of FTY720 could contribute to its favorable therapeutic response in multiple sclerosis.
Department of Neurology, University of Chicago, Chicago, Illinois 60637, USA.
Hye Jung
HJ
Kim
Veronique E
VE
Miron
Danuta
D
Dukala
Richard L
RL
Proia
Samuel K
SK
Ludwin
Maria
M
Traka
Jack P
JP
Antel
Betty
B
Soliven
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D003337:Corpus Callosum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy; D000068876:Fingolimod Hydrochloride; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D003471:Cuprizone; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
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