title: Taming neonatal hypoxic-ischemic brain injury by intranasal delivery of plasminogen activator inhibitor-1.
abstract: OBJECTIVE
  Plasminogen activator inhibitor-I (PAI-1), a ≈50-kDa serine protease inhibitor, markedly reduces the extravascular toxicity of tissue-type plasminogen activator in experimental hypoxic-ischemic (HI) brain injury of newborns. However, the current treatment with PAI-1 requires intracerebroventricle injection to cross the blood-brain barrier, which is an invasive procedure of limited clinical potential. Thus, we tested whether intranasal administration of PAI-1 can bypass blood-brain barrier and mitigate neonatal HI brain injury.
  
  
  METHODS
  Rat pups were subjected to HI, with or without lipopolysaccharide pre-exposure, followed by intranasal delivery of a stable-mutant form of PAI-1 (CPAI).
  
  
  RESULTS
  Immunoblotting showed that CPAI sequentially entered the olfactory bulbs and cerebral cortex after intranasal delivery and reduced ≈75% of brain atrophy in HI or lipopolysaccharide-sensitized HI injury. Mechanistically, CPAI attenuated HI-induced plasminogen activators and lipopolysaccharide/HI-induced nuclear factor-κB signaling, neuroinflammation, and blood-brain barrier permeability.
  
  
  CONCLUSIONS
  Intranasal delivery of CPAI is an effective treatment of experimental HI brain injury of newborns. Clinical application of this experimental therapy merits further investigation.
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center. Cincinnati, OH 45229.|Division of Neurology, Department of Pediatrics; the Center for Neurodegenerative Disease (CND), the Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Dianer
authors.initials: D
authors.lastname: Yang
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center. Cincinnati, OH 45229.|Division of Neurology, Department of Pediatrics; the Center for Neurodegenerative Disease (CND), the Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Yu-Yo
authors.initials: YY
authors.lastname: Sun
authors.affiliation: Division of Neurology, Department of Pediatrics; the Center for Neurodegenerative Disease (CND), the Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center. Cincinnati, OH 45229.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Baumann
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Mark
authors.initials: M
authors.lastname: Warnock
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: Division of Developmental Biology, Department of Pediatrics, Cincinnati's Children's Hospital Medical Center. Cincinnati, OH 45229.|Division of Neurology, Department of Pediatrics; the Center for Neurodegenerative Disease (CND), the Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage* / Q000627:therapeutic use; D015849:Plasminogen Inactivators / Q000008:administration & dosage* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D015849:Plasminogen Inactivators; D015842:Serine Proteinase Inhibitors
keywords: chorioamnionitis; hypothermia; hypoxic-ischemic encephalopathy; intrauterine infection; neonatal encephalopathy; tissue-type plasminogen activator