SPHINGOSINE-1-PHOSPHATE RECEPTOR MODULATION IN NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY

Brain damage by hypoxia-ischemia is a devastating injury to neonatal infants, and can lead to long-term neurological defects, e.g. cerebral palsy. Recent revelations concerning the nature of sphingosine-1-phosphate (S1P) analogs led us to investigate their role in this serious health issue. Discovering the potential effectiveness of FDA approved Fingolimod in ameliorating hypoxia- ischemia brain injury in a neonatal mouse model was the end-goal, building off of reports of its efficacy in inhibiting demyelination induced by cuprizone; as well as the fact that central nervous system cells express S1P-receptors - its target receptor family. Temporal and spatial S1P receptor expression was characterized in developing mouse brains, and hypoxia-ischemia was induced in neonatal mice by cauterization to the right common carotid artery, followed by hypoxia exposure. To mimic neonatal infection and inflammation, mice in this condition additionally underwent Lipopolysaccharide peritoneal injection. Fingolimod was similarly administered, and animals were sacrificed four days post procedure and analyzed for the extent of brain injury. Combined hypoxia-ischemia with Lipopolysaccharide was found to cause hypomyelination in the corpus callosum, striatum, and thalamus, as well as hippocampus neuron damage, more so than hypoxia-ischemia alone. The importance of this and future investigation lies in the need for a consistently effective treatment of newborn injury by ischemia, which, unlike in adults, is yet to be found. We hope these findings will further the pursuit of minimizing the large and deleterious impacts of this type of injury to infants