Effects of hypothermia on oligodendrocyte precursor cell proliferation, differentiation and maturation following hypoxia ischemia in vivo and in vitro

Abstract

Hypoxic-ischemia (HI) not only causes gray matter injury but also white matter injury, leading to severe neurological deficits and mortality, and only limited therapies exist. The white matter of animal models and human patients with HI-induced brain injury contains increased oligodendrocyte precursor cells (OPCs). However, little OPC can survive and mature to repair the injured white matter. Here, we test the effects of mild hypothermia on OPC proliferation, differentiation and maturation. Animals suffered to left carotid artery ligation followed by 8% oxygen for 2h in 7-day-old rats. They were divided into a hypothermic group (rectal temperature 32-33 °C for 48 h) and a normothermic group (36-37 °C for 48 h), then animals were sacrificed at 3, 7, 14 and 42 days after HI surgery. Our results showed that hypothermia successfully enhanced early OL progenitors (NG2(+)) and its proliferation in the corpus callosum (CC) after HI. Late OL progenitor (O4(+)) accumulation decreased accompanied with increased OL maturation which is detected by myelin basic protein (MBP) and proteolipid protein. (PLP) immunostaining and immunoblotting in hypothermia compared to normothermia. Additionally, using an in vitro hypoxic-ischemia model-oxygen glucose deprivation (OGD), we demonstrated that hypothermia decreased preOL accumulation and promoted OPC differentiation and maturation. Further data indicated that OPC death was significantly suppressed by hypothermia in vitro. The myelinated axons and animal behavior both markedly increased in hypothermic- compared to normothermic-animals after HI. In summary, these data suggest that hypothermia has the effects to protect OPC and to promote OL maturation and myelin repair in hypoxic-ischemic events in the neonatal rat brain. This study proposed new aspects that may contribute to elucidate the mechanism of hypothermic neuroprotection for white matter injury in neonatal rat brain injury.

Keywords: Hypothermia; Hypoxic-ischemia; Immature brain; Maturation; Oligodendrocyte precursor.