title: Preferential Protection of Cerebral Autoregulation and Reduction of Hippocampal Necrosis With Norepinephrine After Traumatic Brain Injury in Female Piglets.
abstract: OBJECTIVE
  Traumatic brain injury contributes to morbidity in children and boys is disproportionately represented. Cerebral autoregulation is impaired after traumatic brain injury, contributing to poor outcome. Cerebral perfusion pressure is often normalized by the use of vasopressors to increase mean arterial pressure. In prior studies, we observed that phenylephrine prevented impairment of autoregulation in female but exacerbated in male piglets after fluid percussion injury. In contrast, dopamine prevented impairment of autoregulation in both sexes after fluid percussion injury, suggesting that pressor choice impacts outcome. The extracellular signal-regulated kinase isoform of mitogen-activated protein kinase produces hemodynamic impairment after fluid percussion injury, but the role of the cytokine interleukin-6 is unknown. We investigated whether norepinephrine sex-dependently protects autoregulation and limits histopathology after fluid percussion injury and the role of extracellular signal-regulated kinase and interleukin-6 in that outcome.
  
  
  METHODS
  Prospective, randomized animal study.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  Newborn (1-5 d old) pigs.
  
  
  METHODS
  Cerebral perfusion pressure, cerebral blood flow, and pial artery diameter were determined before and after fluid percussion injury in piglets equipped with a closed cranial window and post-treated with norepinephrine. Cerebrospinal fluid extracellular-signal-regulated kinase mitogen-activated protein kinase was determined by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Norepinephrine does not protect autoregulation or prevent reduction in cerebral blood flow in male but fully protects autoregulation in female piglets after fluid percussion injury. Papaverine-induced dilation was unchanged by fluid percussion injury and norepinephrine. Norepinephrine increased extracellular signal-regulated kinase mitogen-activated protein kinase up-regulation in male but blocked such up-regulation in female piglets after fluid percussion injury. Norepinephrine aggravated interleukin-6 upregulation in males in an extracellular signal-regulated kinase mitogen-activated protein kinase-dependent mechanism but blocked interleukin-6 up-regulation in females after fluid percussion injury. Norepinephrine augments loss of neurons in CA1 and CA3 hippocampus of male piglets after fluid percussion injury in an extracellular signal-regulated kinase mitogen-activated protein kinase-dependent and interleukin-6-dependent manner but prevents loss of neurons in females after fluid percussion injury.
  
  
  CONCLUSIONS
  Norepinephrine protects autoregulation and limits hippocampal neuronal cell necrosis via modulation of extracellular signal-regulated kinase mitogen-activated protein kinase and interleukin-6 after fluid percussion injury in a sex-dependent manner.
authors.affiliation: 1Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA. 2Department of Pharmacology, University of Pennsylvania, Philadelphia, PA. 3Department of Anesthesiology, Pediatrics, and Neurological Surgery, University of Washington, Seattle, WA.
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: Monica S
authors.initials: MS
authors.lastname: Vavilala
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001783:Blood Flow Velocity / Q000502:physiology*; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004298:Dopamine / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D009336:Necrosis; D009638:Norepinephrine / Q000627:therapeutic use*; D011446:Prospective Studies; D011897:Random Allocation; D012737:Sex Factors; D013552:Swine; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*
chemical_list: D015850:Interleukin-6; D014662:Vasoconstrictor Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine; D009638:Norepinephrine