The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors.
The immunomodulator 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720) has promising therapeutic effects in multiple sclerosis (MS), a degenerative disease in which demyelination of the central nervous system is accompanied by death of oligodendrocytes (OLGs), the myelin-producing cells. In vivo phosphorylation of FTY720 generates an agonist for G protein-coupled receptors for sphingosine-1-phosphate, a lipid mediator that plays a crucial role in the stimulation of OLG survival by neurotrophin-3 (NT-3). The mechanisms underlying the action of FTY720 in MS are not clearly understood, although the effects of this drug in autoimmune diseases are thought to stem from its ability to reduce lymphocyte infiltration and inflammation. Interestingly, we now found that FTY720 also has a direct effect on OLG progenitors. Treatment of these cells with FTY720 causes activation of extracellular signal-regulated kinase 1/2 and Akt, accompanied by protection from apoptosis. However, FTY720 also arrested OLG differentiation. Importantly, this effect was counteracted by NT-3, which not only enhanced the survival of OLG progenitors induced by FTY720 but also stimulated their maturation. Altogether, these observations suggest that in addition to its immunosuppressive functions, FTY720 could also have a beneficial effect in MS by direct action on OLG progenitors. However, the finding that FTY720 blocks the differentiation of these cells raises the question of whether MS therapies with FTY720 should include the use of differentiation-enhancing factors such as NT-3. This approach would ensure both protection of existing OLG progenitor pools against immune-mediated insults as well as stimulation of remyelination by enhancing the maturation of these cells.
Coelho
Rochelle P
RP
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Payne
Shawn G
SG
Bittman
Robert
R
Spiegel
Sarah
S
Sato-Bigbee
Carmen
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017628:Microglia / Q000502:physiology; D020933:Neurotrophin 3 / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D011409:Propylene Glycols / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects*; D000099157:Sphingosine Kinase
D048049:Extracellular Signal-Regulated MAP Kinases; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D020933:Neurotrophin 3; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D000099157:Sphingosine Kinase