title: Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia.
abstract: 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.
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Meray
authors.initials: M
authors.lastname: Serdar
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Herz
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Karina
authors.initials: K
authors.lastname: Kempe
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Lumpe
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Reinboth
authors.affiliation: Department of Pediatrics, University of Geneva, Genève, Switzerland.
authors.forename: Stéphane V
authors.initials: SV
authors.lastname: Sizonenko
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Xinlin
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Herrmann
authors.affiliation: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hadamitzky
authors.affiliation: Molecular Neurochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Bochum, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Heumann
authors.affiliation: Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hansen
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.affiliation: Department of Pediatrics, University of Geneva, Genève, Switzerland; Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Yohan
authors.initials: Y
authors.lastname: van de Looij
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Electronic address: ursula.felderhoff@uk-essen.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Müser
authors.affiliation: Department of Pediatrics 1 - Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Electronic address: ivo.bendix@uk-essen.de.
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D018496:Hyperoxia / Q000188:drug therapy* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000008:administration & dosage; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D066127:White Matter / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D010100:Oxygen
keywords: Fingolimod; Hyperoxia; Neonatal brain injury; Oligodendrocyte; White matter development