title: Combined treatment of xenon and hypothermia in newborn rats--additive or synergistic effect?
abstract: BACKGROUND
  Breathing the inert gas Xenon (Xe) enhances hypothermic (HT) neuroprotection after hypoxia-ischemia (HI) in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added) or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7) rats, showed that the combination of mild HT (35°C) and low Xe concentration (20%), both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study.
  
  
  METHODS
  After the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT) NT37°C, HT35°C, HT32°C) or Xe concentrations (0%, 20% or 50%) starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101) of P7 pups were exposed to either HT35°C+Xe0%, NT+Xe20% or a combination of HT35°C+Xe20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side) brain tissue area loss after seven day survival.
  
  
  RESULTS
  Immediate HT32°C (p = 0.042), but not HT35°C significantly reduced brain injury compared to NT37°C. As previously shown, adding immediate Xe50% to HT32°C increased protection. Neither 4 h-delayed Xe20%, nor Xe50% at 37°C significantly reduced brain injury (p>0.050). In addition, neither 4 h-delayed HT35°C alone, nor HT35°C+Xe20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model.
  
  
  CONCLUSIONS
  Combining two treatments that individually were ineffective (delayed HT35°C and delayed Xe20%) did not exert neuroprotection when combined, and therefore did not show a synergistic treatment effect.
authors.affiliation: Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Hemmen
authors.initials: H
authors.lastname: Sabir
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Walløe
authors.affiliation: College of Medicine, Swansea University, Swansea, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Dingley
authors.affiliation: Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Elisa
authors.initials: E
authors.lastname: Smit
authors.affiliation: Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Xun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Marianne
authors.initials: M
authors.lastname: Thoresen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000628:therapy*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013696:Temperature; D013997:Time Factors; D014978:Xenon / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D014978:Xenon