A clinically relevant model and a potential treatment of perinatal hypoxic ischaemic encephalopathy in mice

Abstract

Hypoxia ischaemia (HI) due to neonatal asphyxia is the most common cause of acute mortality and chronic neurological disability. Currently there is no effective means to repair the damaged brain. The aim of this study was to 1) establish a clinically relevant intrauterine model of perinatal hypoxic ischaemic encephalopathy (HIE) in mice, 2) determine whether lipopolysaccharide (LPS) induced maternal systemic inflammation worsened the outcome of neonates who had previously suffered HIE brain damage and 3) use the mouse HIE model to study whether a docosahexaenoic acid (DHA) enriched maternal diet has the potential to alleviate this harmful clinical condition. This is the first time that the intrauterine HI model has been established in mice. Pups exposed to 15 minutes of HI showed a higher mortality rate at 1 hour and those who survived displayed worse short term outcomes. However, the results were inconsistent with regards to the cellular changes observed such as inflammation and apoptosis, histological evidence and long-term neurocognitive outcomes. LPS-induced maternal systemic inflammation combined with HI showed no difference in survival rates compared to HI alone with a lower hypoxia-inducible factor 1-alpha and higher phospho-p38 and phospho-bad levels in the pup brains being observed. A maternal diet enriched with DHA did not result in a better outcome in the DHA + HI pups. The greater mortality rates in both Caesarean section (CS) and HI groups regardless of DHA in the diet indicated that other factors may influence neonatal death rates. Based on these data, this study concludes that the 15 minutes intrauterine HIE model cannot provide sustained damage observed in the mice brain and that the maternal LPS induced systemic inflammation did not show a clear better or worse outcome in the offspring. In addition, no clear neuroprotective effect was seen for the DHA enriched diet group.