Cerebral white matter injury is a leading cause of adverse neurodevelopmental outcome in prematurely born infants involving cognitive deficits in later life. Despite increasing knowledge about the pathophysiology of perinatal
brain injury, therapeutic options are limited. In the adult
demyelinating disease multiple sclerosis the
sphingosine-1-phosphate (
S1P) receptor modulating substance
fingolimod (
FTY720) has beneficial effects. Herein, we evaluated the neuroprotective potential of
FTY720 in a neonatal model of
oxygen-toxicity, which is associated with hypomyelination and impaired neuro-cognitive outcome. A single dose of
FTY720 (1mg/kg) at the onset of neonatal
hyperoxia (24h 80%
oxygen on postnatal day 6) resulted in improvement of neuro-cognitive development persisting into adulthood. This was associated with reduced microstructural white matter abnormalities 4 months after the insult. In search of the underlying mechanisms potential non-classical (i.e. lymphocyte-independent) pathways were analysed shortly after the insult, comprising modulation of oxidative stress and local inflammatory responses as well as myelination, oligodendrocyte degeneration and maturation. Treatment with
FTY720 reduced
hyperoxia-induced oxidative stress, microglia activation and associated pro-inflammatory
cytokine expression. In vivo and in vitro analyses further revealed that
oxygen-induced hypomyelination is restored to control levels, which was accompanied by reduced oligodendrocyte degeneration and enhanced maturation. Furthermore,
hyperoxia-induced elevation of
S1P receptor 1 (S1P1)
protein expression on in vitro cultured oligodendrocyte precursor cells was reduced by activated
FTY720 and protection from degeneration is abrogated after selective S1P1 blockade. Finally, FTY720s' classical mode of action (i.e. retention of immune cells within peripheral lymphoid organs) was analysed demonstrating that
FTY720 diminished circulating lymphocyte counts independent from
hyperoxia. Cerebral immune cell counts remained unchanged by
hyperoxia and by
FTY720 treatment. Taken together, these results suggest that beneficial effects of
FTY720 in neonatal
oxygen-induced
brain injury may be rather attributed to its anti-oxidative and anti-inflammatory capacity acting in concert with a direct protection of developing oligodendrocytes than to a modulation of peripheral lymphocyte trafficking. Thus,
FTY720 might be a potential new therapeutic option for the treatment of neonatal
brain injury through reduction of white matter damage.