Epigenetic modulation in response to perinatal asphyxia

Abstract

Perinatal asphyxia is one of the leading causes of fetal death and neurological problems among neonates. Currently, the only treatment is therapeutic hypothermia, which is a challenge for medicine to identify possible cases of asphyxia earlier and to apply more efficient neuroprotective measures to minimise the sequelae. Asphyxia is characterised by an initial ischaemic hypoxic event and a subsequent restoration of blood flow, both of which are associated with a complex pathophysiology characterised by excitotoxicity, mitochondrial dysfunction, inflammation, apoptosis, and cellular necrosis in immature brains. The brain injury produced is time-dependent and the clinical manifestation of perinatal asphyxia is called hypoxic-ischaemic encephalopathy, which depending on its degree of severity will be a candidate for therapeutic hypothermia or not. In turn, epigenetic modifications also occur as a measure of cellular adaptation to hypoxic conditions. This leads to an alteration in gene expression in which, at a global level, there is a silencing of genes, but the expression of certain genes involved in cell metabolism or in increasing oxygen availability, for example, through erythropoietin, is enhanced. Among the most relevant epigenetic processes are the hypoxia-inducible factor HIF-1, DNA methylation, microRNAs, and histone modifications. Although the epigenetics involved in perinatal asphyxia contribute to adaptation to new oxygen conditions, such changes can also add to brain damage, so studies are currently underway to develop drugs to reverse these epigenetic alterations. In this review, the most important features of perinatal asphyxia, as well as the most relevant epigenetic modifications associated with a hypoxic ischaemic event, are presented.