Novel cytoprotective role of FTY720 in oligodendrocytes

ROCHELLE P. COELHO; HARSIMRAN S. SAINI; EMILSE S. SANCHEZ; SARAH SPIEGEL; CARMEN SATO-BIGBEE

Simposio; Daniel T. Watts Research Poster Symposium; 2005

Myelin, the multi lamellar membrane that surrounds axons allowing the rapid saltatory conduction of nerve impulses, is made by oligodendrocytes (OLGs) and their death is an important feature of degenerative diseases like Multiple Sclerosis (MS). Thus, understanding the mechanisms that control OLG survival may provide clues for MS therapies. We showed that neurotrophin-3 (NT-3) stimulates OLG survival by a mechanism that involves CREB transcription factor activation and stimulation of the antiapoptotic gene Bc1-2. Interestingly, we found that this process, which requires ERK and PKC activities, also involves sphingosine kinase I (SphKI), an enzyme that generates the lipid mediator sphingosine-I-phosphate. Moreover, inhibition of SphKl expression by siRNA abolishes NT -3 dependent OLG survival. These observations lead us to study the effect of FTY720, a drug currently used in trials for MS treatment. Phosphorylated FTY720 appears to work as an SIP analog, blocking lymphocyte migration from the lymph nodes. However, we found that treatment of OLGs with FTY720 causes rapid ERK activation and 50% reduction in apoptotic cell death in response to growth factor deprivation. This suggests that the FTY720 effect on remyelination may not only involve blockade of lymphocyte infiltration but may also result from direct stimulation of OLG survival. Future work aims at elucidating the pathways involved in the FTY720-mediated cytoprotection, further supporting the use of this drug in MS, in combination with other similar acting agents like NT-3.