Mode of action of Fingolimod on neurons: the role of the sphingosine 1-phosphate receptor 1

Brain-derived neurotrophic factor (BDNF) is a secretory protein known to be essential for brain function, including key aspects of synaptic transmission. Its levels are decreased in a number of conditions including neurodegenerative diseases, thus generating a need for well-tolerated drugs increasing BDNF levels in the brain. The sphingosine analogue fingolimod, also designated FTY720, is one of a still very small number of drugs readily diffusing into the brain and extensively used in humans following its approval for the treatment of multiple sclerosis. It acts as a functional antagonist on the G protein-coupled receptor sphingosine 1-phosphate receptor 1 (S1P1R) thereby preventing the exit of lymphocytes from lymph nodes. Recently, FTY720 has been shown to increase BDNF levels in the brain and the main objective of the work was to investigate whether S1P1R plays a role in the action of the drug on neurons. This study reports on the successful generation of mutant neurons lacking S1P1R from mouse embryonic stem cells, using a modified differentiation protocol. While the interpretation of the data was complicated by a high variability encountered in the culture system, preliminary data suggests a role of S1P1R in the long-term effects of pFTY720 on BDNF levels in vitro. As the BDNF gene has been recently reported to be not only expressed by neurons, but also by megakaryocytes, FTY720-dependent effects were also investigated in primary rat megakaryocytes. This work establishes that sphingosine receptors were found to be expressed at the mRNA level in ES cell-derived neurons and primary rat megakaryocytes and reveals an unexpected complexity of FTY720 signalling in these cells