title: Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia.
abstract: BACKGROUND
  The general anesthetic gas xenon is neuroprotective and is undergoing clinical trials as a treatment for ischemic brain injury. A small number of molecular targets for xenon have been identified, the N-methyl-D-aspartate (NMDA) receptor, the two-pore-domain potassium channel TREK-1, and the adenosine triphosphate-sensitive potassium channel (KATP). However, which of these targets are relevant to acute xenon neuroprotection is not known. Xenon inhibits NMDA receptors by competing with glycine at the glycine-binding site. We test the hypothesis that inhibition of the NMDA receptor at the glycine site underlies xenon neuroprotection against hypoxia-ischemia.
  
  
  METHODS
  We use an in vitro model of hypoxia-ischemia to investigate the mechanism of xenon neuroprotection. Organotypic hippocampal brain slices from mice are subjected to oxygen-glucose deprivation, and injury is quantified by propidium iodide fluorescence.
  
  
  RESULTS
  We show that 50% atm xenon is neuroprotective against hypoxia-ischemia when applied immediately after injury or after a delay of 3 h after injury. To validate our method, we show that neuroprotection by gavestinel is abolished when glycine is added, confirming that NMDA receptor glycine site antagonism underlies gavestinel neuroprotection. We then show that adding glycine abolishes the neuroprotective effect of xenon, consistent with competitive inhibition at the NMDA receptor glycine site mediating xenon neuroprotection.
  
  
  CONCLUSIONS
  We show that xenon neuroprotection against hypoxia- ischemia can be reversed by increasing the glycine concentration. This is consistent with competitive inhibition by xenon at the NMDA receptor glycine site, playing a significant role in xenon neuroprotection. This finding may have important implications for xenon's clinical use as an anesthetic and neuroprotectant.
authors.affiliation: Biophysics Section, Blackett Laboratory, Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Banks
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Franks
authors.forename: Robert
authors.initials: R
authors.lastname: Dickinson
mesh_terms: D018685:Anesthetics, Inhalation / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004396:Coloring Agents; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D005998:Glycine / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology; D006931:Hyperbaric Oxygenation; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000517:prevention & control*; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors; D009924:Organ Culture Techniques; D011419:Propidium; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014978:Xenon / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D018685:Anesthetics, Inhalation; D004396:Coloring Agents; D018691:Excitatory Amino Acid Antagonists; D018684:Glycine Agents; D007211:Indoles; D018696:Neuroprotective Agents; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D011419:Propidium; D014978:Xenon; D005947:Glucose; D005998:Glycine