Melatonin improves short and long-term neurobehavioral deficits and attenuates hippocampal impairments after hypoxia in neonatal mice.

Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurobehavioral abnormalities. The purpose of this study was to determine whether administration of melatonin, starting at 1h before hypoxia and then every 24 h for 3 days, influences short and long-term neurobehavioral development and hippocampal impairments in postnatal day 1 mice subjected to hypoxia (5% oxygen and 95% nitrogen for 120 min). Melatonin significantly attenuated hypoxia-induced neurobehavioral deficits, including sensorimotor performance, locomotor functions, and hyperactivity up to two weeks after hypoxia insult. The above-mentioned functional benefits of melatonin were associated with attenuation of cell death in the hippocampus. Importantly, melatonin improved learning and memory performance in the Morris water test, as associated with significantly increased proliferating cells (BrdU-positive cells) and differentiating neuroblasts (doublecortin-positive neuroblasts) in the hippocampus of hypoxic animals at 30 days after hypoxia. In addition, melatonin significantly decreased microglial activation and overproduction of pro-inflammatory mediators (tumor necrosis factor-α, interleukin-1β and nitric oxide) from 3 to 30 days after hypoxia, possibly by inhibiting NF-κB activation in the hippocampus. The present results show that melatonin has short- and long-term protective effects against hypoxia-induced neurobehavioral deficits in the neonatal mouse. These beneficial effects are associated with increasing neurogenesis and attenuation of cell death and inflammatory responses in the hippocampus.