Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia

Ann Neurol. 2005 Aug;58(2):182-93. doi: 10.1002/ana.20547.

Abstract

Perinatal asphyxia can result in neuronal injury with long-term neurological and behavioral consequences. Although hypothermia may provide some modest benefit, the intervention itself can produce adverse consequences. We have investigated whether xenon, an antagonist of the N-methyl-D-aspartate subtype of the glutamate receptor, can enhance the neuroprotection provided by mild hypothermia. Cultured neurons injured by oxygen-glucose deprivation were protected by combinations of interventions of xenon and hypothermia that, when administered alone, were not efficacious. A combination of xenon and hypothermia administered 4 hours after hypoxic-ischemic injury in neonatal rats provided synergistic neuroprotection assessed by morphological criteria, by hemispheric weight, and by functional neurological studies up to 30 days after the injury. The protective mechanism of the combination, in both in vitro and in vivo models, involved an antiapoptotic action. If applied to humans, these data suggest that low (subanesthetic) concentrations of xenon in combination with mild hypothermia may provide a safe and effective therapy for perinatal asphyxia.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Asphyxia / prevention & control*
  • Blotting, Western / methods
  • Body Temperature / physiology
  • Brain / drug effects
  • Brain / pathology
  • Caspase 3
  • Caspases / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian
  • Excitatory Amino Acid Antagonists / pharmacology
  • Flow Cytometry / methods
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / radiation effects
  • Glucose / deficiency
  • Hypothermia*
  • Hypoxia
  • Hypoxia-Ischemia, Brain / physiopathology
  • Hypoxia-Ischemia, Brain / therapy
  • Immunohistochemistry / methods
  • Indoles / pharmacology
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Necrosis / therapy
  • Neurons / drug effects
  • Neurons / physiology
  • Neuroprotective Agents / therapeutic use*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function / drug effects
  • Temperature
  • Time Factors
  • Xenon / therapeutic use*
  • bcl-2-Associated X Protein
  • bcl-X Protein

Substances

  • 3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid
  • Bcl2l1 protein, mouse
  • Bcl2l1 protein, rat
  • Excitatory Amino Acid Antagonists
  • Indoles
  • Neuroprotective Agents
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Xenon
  • L-Lactate Dehydrogenase
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Glucose