Abstract Details

Title Effects of S1P Receptor Modulator FTY720 on Human Oligodendrocyte Progenitor Cell Differentiation

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 150

Objective

Background BACKGROUND: FTY720 (Fingolimod/Gilenya) is a sphingosine-1-phosphate receptor (S1PR) modulator used clinically on a daily basis. The drug readily accesses the CNS. Adding FTY720 phosphate (FTY720p) in vitro modulates initial process outgrowth in cultured human oligodendrocytes and progenitors (Miron 2008). When added every 3 days over 4 weeks, it enhances differentiation and axon ensheathment of oligodendrocyte progenitor cells (OPCs) that are co-cultured with rat dorsal root ganglia neurons (DRGNs) (Cui ECTRIMS 2011). Repeated daily application of FTY720p to human astrocytes inhibits extracellular-signal-regulated kinase (ERK) phosphorylation (pERK); however, S1PR internalized by FTY720 results in persistent signaling (Mullershausen, 2009; Wu, ECTRIMS 2012).

Design/Methods DESIGN/METHODS: For co-cultures with rat DRGNs, OPCs were selected from 15-18 gestational week human brain samples using PDGFR? antibody coated immuno-magnetic beads. FTY720p or S1P (all 50 nM) were added either daily or every 3 days for 4 weeks. For signaling experiments, OPCs were selected using the A2B5 antibody (to obtain sufficient cells). FTY720 or S1P were added at culture outset or daily over 3 days. pERK was determined by Western blotting.

Results RESULTS: In OPC-DRGN co-cultures, both the numbers of O1+ and MBP+ cells as well as ensheathed axons were increased with FTY720p and S1P given either daily or every three days. In the dissociated cell cultures, a single addition of FTY720p desensitized the pERK signaling response for >24 hours with recovery observed by 72 hours. Repeated daily FTY720p treatment maintained receptor desensitization.

Conclusions CONCLUSIONS: Our results indicate that daily treatment with FTY720 can promote OPC differentiation even while maintaining external S1PR desensitization.

Authors/Disclosures
Qiao Ling Cui, MD PRESENTER	No disclosure on file
Tiffany Shih, MD, PhD (UC Davis Neurology)	Dr. Shih has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Jack P. Antel, MD, FAAN (Montreal Neurologic Hospital)	Dr. Antel has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for sanofi, roche, biogen, wave,nervgen. The institution of Dr. Antel has received research support from Novartis canada bristol myers squib. Dr. Antel has a non-compensated relationship as a past president with ACTRIMS that is relevant to AAN interests or activities.

��ɫ��

��ɫ��