A new study in mouse cortical neurons suggests that fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator currently used to treat MS, may reduce beta-amyloid neurotoxicity (Doi et al. PLoS One 2013;8:e6; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3625222/pdf/pone.0061988.pdf).

Cortical neurons were shown to express all S1P subtypes. Treatment with fingolimod-P 100 pM three hours prior to administration of beta-amyloid protected neurons from severe beta-amyloid-induced neurotoxicity. Subsequent experiments indicated that this neuroprotective effect was due to fingolimod-P-induced production of brain-derived neurotrophic factor (BDNF). This effect was inhibited in a dose-dependent manner by the addition of a BDNF scavenger, and completely blocked when BDNF-TrkB signalling was interrupted with a TrkB or ERK1/2 inhibitor. The addition of BDNF alone had a similar effect on beta-amyloid-induced neurotoxicity as fingolimod-P.

This is the first report to suggest that fingolimod-P protects against beta-amyloid-induced neurotoxicity. Previous laboratory studies have shown that fingolimod-P enhances remyelination (Miron et al. Am J Pathol 2010;176:2682-2694). Other non-immunological effects of fingolimod in the CNS may include downregulation of S1P1 signalling from astrocytes, which reduces astrogliosis and clinical severity in EAE (Choi et al. PNAS USA 2011;108:751-756; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3021041/pdf/pnas.201014154.pdf)

For a recent review of S1P1 signalling in the CNS see Groves et al. J Neurol Sci 2013;328:9-18.

Comment
Dr. Yves Bacher: Is this a start of an interesting development? There is a long way between cell culture and clinical application and only the future can tell. But it looks promising…