Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia

Autor: Ursula Felderhoff-Müser, Wiebke Hansen, Ivo Bendix, Josephine Herz, Marco Sifringer, Katharina Lumpe, Karina Kempe, Ralf Herrmann, Martin Hadamitzky, Xinlin Hou, Yohan van de Looij, Meray Serdar, Stéphane Sizonenko, Barbara S. Reinboth, Rolf Heumann
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Medizin
Sphingosine/analogs & derivatives/metabolism
medicine.disease_cause
Nerve Fibers
Myelinated
Cognition Disorders/metabolism/pathology/prevention & control
Behavioral Neuroscience
Microglia/drug effects/metabolism/pathology
Random Allocation
0302 clinical medicine
Sphingosine
Pregnancy
hemic and lymphatic diseases
CIBM-AIT
Hyperoxia
ddc:618
Nerve Fibers
Myelinated/drug effects
Microglia
Brain
White Matter
Fingolimod
Oligodendroglia
Receptors
Lysosphingolipid
medicine.anatomical_structure
Female
medicine.symptom
medicine.drug
Oligodendroglia/drug effects/metabolism/pathology
Immunology
Biology
Neuroprotection
White matter
03 medical and health sciences
Oxygen/administration & dosage
medicine
Animals
Brain/metabolism
Rats
Wistar
Fingolimod Hydrochloride/therapeutic use
White Matter/drug effects/metabolism/pathology
Fingolimod Hydrochloride
Endocrine and Autonomic Systems
Multiple sclerosis
Lysophospholipids/metabolism
Neonatal brain injury
medicine.disease
Oligodendrocyte
Rats
Oxygen
030104 developmental biology
Diffusion Magnetic Resonance Imaging
Receptors
Lysosphingolipid/antagonists & inhibitors/metabolism
Animals
Newborn
Lysophospholipids
White matter development
Cognition Disorders
Hyperoxia/drug therapy/pathology
030217 neurology & neurosurgery
Oxidative stress
Zdroj: Brain, behavior, and immunity, Vol. 52 (2016) pp. 106-19
ISSN: 1090-2139
Popis: 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 4months 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.
Databáze: OpenAIRE
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