Melatonin attenuates hypoxia-induced ultrastructural changes and increased vascular permeability in the developing hippocampus

Hypoxic injury in the perinatal period may be involved in damaging the developing hippocampus. The damage may be mediated by excess production of vascular endothelial growth factor (VEGF) and nitric oxide (NO). We examined the hippocampus of neonatal Wistar rats subjected to hypoxia for VEGF and NO production. The mRNA and protein expression of hypoxia inducible factor-1 alpha, endothelial, neuronal, inducible nitric oxide synthase and VEGF was found to be up-regulated significantly after the hypoxic exposure. Tissue VEGF concentration and NO production were also increased. By electron microscopy, swollen dendrites, vacuolated axons and hypertrophic astrocyte end feet associated with blood vessels were observed in hypoxic animals. In hypoxic rats, the passage of rhodamine isothiocyanate (RhIC) and horseradish peroxidase, administered intraperitoneally or intravenously, was observed through vascular walls. Furthermore, immunoglobulin G was localized in the neuropil and neurons. We suggest that increased VEGF and NO production in hypoxia had resulted in increased vascular permeability, leading to structural alteration of the dendrites and axons. Melatonin administration reduced VEGF and NO levels as well as leakage of RhIC, suggesting that it has a therapeutic potential in reducing hypoxia-associated damage in the developing hippocampus.