Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury

Epidemiological studies show a markedly increased risk of cerebral palsy fo llowing the combined exposure of infection and birth asphyxia. However, the underlying mechanisms of this increased vulnerability remain unclear. We h ave examined the effects of a low dose of bacterial endotoxin on hypoxic-is chaemic injury in the immature brain of rats. Bacterial endotoxin (lipopoly saccharide 0.3 mg/kg) was administered to 7-day-old rats 4 h prior to unila teral hypoxia-ischaemia and the neurological outcome was determined 3 days later. Rectal temperature and cerebral blood flow was measured during the s tudy and the expression of CD14 and toll-like receptor-4 mRNA in the brain was examined. We found that a low dose of endotoxin dramatically sensitizes the immature brain to injury and induces cerebral infarction in response t o short periods of hypoxia-ischaemia that by themselves caused no or little injury. This effect could not be explained by a reduction in cerebral bloo d flow or hyperthermia. In association with the sensitization of injury we found an altered expression of CD14 mRNA and toll-like receptor-4 mRNA in t he brain. These results suggest that the innate immune system may be involv ed in the vulnerability of the immature brain following the combination of infection and hypoxia-ischaemia.