Sphingosin-1-phosphate-receptor modulation reduces hyperoxia mediated brain injury

Abstract

Background: Clinical and experimental studies revealed that oxygen which is widely used in neonatal medicine for resuscitation and treatment of pulmonary hypertension triggers widespread neural apoptosis leading to gray and white matter damage. Within the last years it became evident that modulation of the sphingosine-1phosphate (S1P)-receptor system by the S1P analogue FTY720, shows immunomodulatory and neuroprotective capacities. Since we recently show a detrimental role of hyperoxia in white matter structures of the developing rodent brain, we investigated whether FTY720 might modulate cell death of primary oligodendrocytes and shows therapeutic potential in the developing white matter in vivo. Material and methods: Primary oligodendrocyte precursor cells (pOLN) were generated from mixed glia cultures, obtained from 2 days old Spraque–Dawley rat brains. pOLNs were cultivated for 3– 4 days and were treated with biological active FTY720. Cell death was assessed by flow cytometry (Annexin-V, 7AAD). In order to evaluate the therapeutic potential of FTY720 in the context of hyperoxia-mediated brain injury in vivo we administered 1 mg/kg FTY720 i.p. to six days old (P6) Wistar rats prior to hyperoxia (24 h, 80% oxygen) and analysed oligodendrocyte degeneration and differentiation via immunohistochemistry and western blot at P7 and P11. To detect potential long-term changes regarding motorcognitive development we performed animal behaviour studies focusing on general motor activity and spatio-temporal learning and memory function in adolescent and young adult rats. Summary and conclusion: In the context of hyperoxia-mediated brain injury we provide evidence for an anti-apoptotic capacity of FTY720. Furthermore, we demonstrate a recovery in the differentiation potential of developing oligodendrocytes and an improvement in the long-term neuro-developmental outcome of rats suffering from oxygen toxicity. Our data indicate that FTY20 may have beneficial effects in preterm infants which are exposed to non-physiological elevated oxygen concentrations.