Effects of Preoperative Hypoxia on White Matter Injury Associated with Cardiopulmonary Bypass in a Rodent Hypoxic and Brain Slice Model

BACKGROUND: White matter (WM) injury is common after cardiopulmonary bypass or deep hypothermic circulatory arrest (DHCA) in neonates who have cerebral immaturity secondary to in utero hypoxia. The mechanism remains unknown. We investigated effects of preoperative-hypoxia on DHCA-induced WM-injury using a combined experimental paradigm in rodents. METHODS: Mice were exposed to hypoxia (Pre-Hypoxia). Oxygen-glucose deprivation (OGD) was performed under three temperatures to simulate brain conditions of DHCA including ischemia-reperfusion/reoxygenation under hypothermia. RESULTS: WM-injury in Pre-Normoxia was identified after 35°C-OGD. In Pre-Hypoxia, injury was displayed in all groups. Among oligodendrocyte stages, the pre-oligodendrocyte was the most susceptible while the oligodendrocyte progenitor was resistant to insult. When effects of Pre-Hypoxia were assessed, injury of mature oligodendrocytes and oligodendrocyte progenitors in Pre-Hypoxia significantly increased compared with Pre-Normoxia, indicating that mature oligodendrocytes and progenitors which had developed under hypoxia had greater vulnerability. Conversely, damage of oligodendrocyte progenitors in Pre-Hypoxia were not identified after 15°C-OGD, suggesting that susceptible oligodendrocytes exposed to hypoxia are protected by deep hypothermia. DISCUSSION: Developmental alterations due to hypoxia result in an increased WM susceptibility to injury. Promoting WM regeneration by oligodendrocyte progenitors after earlier surgery using deep hypothermia is the most promising approach for successful WM development in CHD patients.