Perinatal Brain Injury: Mechanism and potential pharmacological therapies - The role of SIRT1 in the neuroprotective effect of Melatonin and of Endothelin-1 in Oligodendrocyte Progenitor Cell Development

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of perinatal brain injury in neonates and is associated with severe and long-term neurodisabilities. Despite the high level of infants affected every year by HIE and the severe long-term outcomes associated with this pathology, there are very few preventative or protective treatments available for the patients. We found that Melatonin, a neurohormone constitutively secreted by the pineal gland in the brain, acts as a neuroprotective agent in a neonatal rat model of hypoxia-ischemia (HI) brain injury 1 hours after the insult. Pharmacological doses of Melatonin, administered five minutes after the end of the HI insult, preserved the expression of the nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase Sirtuin 1 (SIRT1), resulting in p53 deacetylation and apoptosis inhibition. Furthermore, these effects were concomitant with autophagy activation, demonstrated by changes in LC3 II and p62 expression. Overall, these results demonstrate that Melatonin treatment immediately following HI is able to prevent the initiation of multiple signaling cascades that lead to severe brain damage. The human preterm brain is particularly susceptible to cerebral white matter injury, which involves maturation dependent vulnerability of the oligodendrocyte lineage with selective degeneration of late oligodendrocyte progenitor cells (OPCs). The cellular and molecular processes underlying early postnatal white matter development still need to be explored. We found that Endothelin-1 (ET-1), a secreted signaling peptide exhibiting vasoconstrictive properties, is a novel regulator of OPC proliferation in the developing postnatal SVZ. Our ex vivo studies showed that 100nM ET-1 treatment is able to expand the OPC pool, specifically enhancing the overall proliferative ratio of NG2+ cells. In order to test ET-1 overexpression in an in vivo model of the developing SVZ, we successfully overexpressed ET-1 in neonatal mice using electroporation. This in vivo model is a great resource for future studies that will investigate the functional role of ET-1 signaling in NSC and OPC development in the SVZ. Lastly, we characterized the expression pattern of the ET-1 pathway proteins in the piglet SVZ, confirming the high expression of ET-1 and its receptor Ednrb in the SVZ of a higher order animal model with a gyrencephalic brain.