Dexamethasone prevents long-lasting learning impairment following a combination of lipopolysaccharide and hypoxia-ischemia in neonatal rats

Objective: There are no established therapies for preventing or rescuing perinatal infection or inflammation-induced perinatal brain damage. We administered dexamethasone (DEX), a synthetic corticosteroid anti -inflammatory drug, to neonatal rats in a model of such damage induced by a combination of lipopolysaccharide (LPS) and hypoxia-ischemia (HI), which produces characteristic histologic and behavioral abnormalities. Study design: Four hours after the injection of LPS (1 mg/kg, i.p.), 7-day-old Wistar rat pups were subjected to unilateral HI for I hour according to Levine's procedure. Injections of 0.5 mg/ kg of dexamethasone (DEX-treated group, n = 15) or saline, (saline-treated group, n = 15) were. given 4 hours before HE A sham-operated control group received neither LPS nor HI (n = 15). We chose rats of this age because their stage of brain maturation is similar to the human neonate. Over the 7 to 16 weeks after treatment, a choice reaction time (CRT) task was used for assessment of attention processes in each group, an 8-arm radial maze task was used to test short-term memory, and a water maze task was used to test long-term memory. In the CRT task, the reward food was released when the tested animal correctly pressed a lever on the. side of an illuminating lamp. The correct and incorrect lever pressings were counted. In the 8-arm radial maze task, rats were allowed to move freely, seeking a reward of food placed at the end of I arm. An error was defined as the choice of an arm that had already been visited. In the water maze, rats had to swim to seek a concealed platform as aversive escape motivation. At 19 weeks, the rats were euthanized, the brain was removed, sectioned coronally, and the volume of each part was measured. Results: The striatum, cortex, and hippocampus showed reductions in volume in the salinetreated group (42.7%, 49.2%, and 34.9% decreases compared with the sham-operated controls, respectively), but this was not observed in the DEX-treated group. All learning and memory processes were impaired with the combination of LPS and HI treatment, but these deficits were almost completely prevented by DEX treatment. Conclusion: Dexamethasone is a promising candidate for prevention of infection and inflammation-induced perinatal brain damage. The impact of dexamethasone identifies potential therapeutic pathways once the mechanism of dexamethasone's protection is determined. (C) 2005 Elsevier Inc. All rights reserved.