Impact of hyperthermia on inflammation-related perinatal brain injury.

In a rat model of perinatal inflammation and hypoxia, we investigated the impact of hyperthermia on the deleterious events which are commonly associated with chorioamnionitis. Late-pregnancy gestational day 20 rats received a single injection of either lipopolysaccharide (LPS) Escherichia coli endotoxin or saline. The offspring were born 24-36 h later at full term. The pups underwent hypoxia on the first postnatal day (PND1) immediately after which they were maintained at a planned target temperature for 2 h, before being returned to the dams. The pups were sacrificed on PND5 and the brain tissue was examined. Results showed that LPS alone or in combination with hypoxia was well tolerated. The additional stress of moderate hyperthermia (39°C for 2 h) on PND1 resulted in (a) a significant increase in brain reactive nitrogen species (RNS), (b) a significant increase in caspase-3 activity, (c) a significant increase in c-jun, bax and bcl-2 gene expression and (d) a significant increase in apoptotic cells in the CA1 region of the hippocampus. Hyperthermia was also associated with reduced growth over the ensuing 4 days in a small number of pups. In this model of perinatal inflammation, we demonstrated that brief hyperthermia when superimposed on a perinatal inflammation stimulus and hypoxia led to brain injury while either inflammation alone, or combined inflammatory stimulus and hypoxia did not cause significant damage.