title: Melatonin attenuates hypoxia-induced ultrastructural changes and increased vascular permeability in the developing hippocampus.
abstract: 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-1alpha, 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.
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, Blk MD10, 4 Medical Drive, National University of Singapore, Singapore. antkaurc@nus.edu.sg
authors.forename: Charanjit
authors.initials: C
authors.lastname: Kaur
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Sivakumar
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.forename: Feng Ru
authors.initials: FR
authors.lastname: Tang
authors.forename: Eng Ang
authors.initials: EA
authors.lastname: Ling
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006735:Horseradish Peroxidase; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D046529:Microscopy, Electron, Transmission; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012235:Rhodamines; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D012235:Rhodamines; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C027755:rhodamine isothiocyanate; D006735:Horseradish Peroxidase; D019001:Nitric Oxide Synthase; D008550:Melatonin