title: Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism.
abstract: We have recently shown that increased hydrogen peroxide (H2O2) generation is involved in hypoxia-ischemia (HI)-mediated neonatal brain injury. H2O2 can react with free iron to form the hydroxyl radical, through Fenton Chemistry. Thus, the objective of this study was to determine if there was a role for the hydroxyl radical in neonatal HI brain injury and to elucidate the underlying mechanisms. Our data demonstrate that HI increases the deposition of free iron and hydroxyl radical formation, in both P7 hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD), and the neonatal rat exposed to HI. Both these processes were found to be nitric oxide (NO) dependent. Further analysis demonstrated that the NO-dependent increase in iron deposition was mediated through increased transferrin receptor expression and a decrease in ferritin expression. This was correlated with a reduction in aconitase activity. Both NO inhibition and iron scavenging, using deferoxamine administration, reduced hydroxyl radical levels and neuronal cell death. In conclusion, our results suggest that increased NO generation leads to neuronal cell death during neonatal HI, at least in part, by altering iron homeostasis and hydroxyl radical generation.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Harris
authors.affiliation: Division of Translational and Regenerative Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.affiliation: Division of Translational and Regenerative Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Xutong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Translational and Regenerative Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA. Electronic address: steveblack@email.arizona.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D003470:Culture Media / Q000737:chemistry; D003676:Deferoxamine / Q000494:pharmacology; D005293:Ferritins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017665:Hydroxyl Radical / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D007501:Iron / Q000378:metabolism*; D008867:Microtomy; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D003470:Culture Media; D011990:Receptors, Transferrin; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D005293:Ferritins; D007501:Iron; D000154:Aconitate Hydratase; D005947:Glucose; D003676:Deferoxamine; D019331:NG-Nitroarginine Methyl Ester
keywords: Hydroxyl radical; Hypoxia–ischemia; Iron; Neonatal brain; Neuronal cell death; Nitric oxide