Hyperbaric oxygenation reduces long-term brain injury and ameliorates behavioral function by suppression of apoptosis in a rat model of neonatal hypoxia-ischemia

Abstract

Neonatal hypoxia-ischemia (HI) produces neurodegeneration and brain injury, and leads to behavioral and cognitive dysfunction. Hyperbaric oxygen (HBO) treatment may potentially be neuroprotective in HI injury. The aim of this study was to examine any neuroprotection by HBO treatment on long-term neurological function in the rat model of neontatal HI. Seven-day-old rats were subjected to HI or sham surgery. HBO treatment was administered (2.5 ATA for 90 min) 1h after hypoxia exposure. Sensorimotor (grip test and rota-rod) and cognitive tests (inhibitory avoidance and Morris water maze) were performed at postnatal day 28 to day 60. The extent of brain damage was determined by histological evaluation. Apoptosis, caspase-3 and apoptosis inducing factor (AIF) expression were assessed by immunohistochemistry 12, 24, and 48 h after HI. HI-treated animals had significantly worse sensorimotor and cognitive performances than those in the Sham group. HBO treatment led to significant improvements in neurobehavioral functions compared to the HI group, especially for cognitive performances. Morphological evaluation revealed a remarkable recovery of brain injury in the HBO group. Furthermore, the improvements in neurobehavioral impairments were correlated with the reduction in lesion size of the hippocampus and cerebral cortex. The proportion of apoptotic cells significantly increased with time after HI, and HBO significantly inhibited apoptotic cell death. The proportion of caspase-3 positive cells and nuclear AIF translocation increased and peaked at 24h after HI injury. HBO-treated rats showed decreased expression of these proteins compared to HI-treated animals. In conclusion, our results suggested that HBO treatment was effective in promoting long-term functional and histological recovery against neonatal HI brain injury. HBO-induced neuroprotection was associated with suppression of apoptosis by inhibiting caspase-3 and AIF-mediated pathways. Further studies evaluating its associated molecular and cellular mechanism are needed.