title: Interactions between nitrous oxide and tissue plasminogen activator in a rat model of thromboembolic stroke.
abstract: BACKGROUND
  Preclinical evidence in rodents has suggested that inert gases, such as xenon or nitrous oxide, may be promising neuroprotective agents for treating acute ischemic stroke. This has led to many thinking that clinical trials could be initiated in the near future. However, a recent study has shown that xenon interacts with tissue-type plasminogen activator (tPA), a well-recognized approved therapy of acute ischemic stroke. Although intraischemic xenon inhibits tPA-induced thrombolysis and subsequent reduction of brain damage, postischemic xenon virtually suppresses both ischemic brain damage and tPA-induced brain hemorrhages and disruption of the blood-brain barrier. The authors investigated whether nitrous oxide could also interact with tPA.
  
  
  METHODS
  The authors performed molecular modeling of nitrous oxide binding on tPA, characterized the concentration-dependent effects of nitrous oxide on tPA enzymatic and thrombolytic activity in vitro, and investigated the effects of intraischemic and postischemic nitrous oxide in a rat model of thromboembolic acute ischemic stroke.
  
  
  RESULTS
  The authors demonstrate nitrous oxide is a tPA inhibitor, intraischemic nitrous oxide dose-dependently inhibits tPA-induced thrombolysis and subsequent reduction of ischemic brain damage, and postischemic nitrous oxide reduces ischemic brain damage, but in contrast with xenon, it increases brain hemorrhages and disruption of the blood-brain barrier.
  
  
  CONCLUSIONS
  In contrast with previous studies using mechanical acute stroke models, these data obtained in a clinically relevant rat model of thromboembolic stroke indicate that nitrous oxide should not be considered a good candidate agent for treating acute ischemic stroke compared with xenon.
authors.affiliation: Université de Caen - Basse Normandie, Centre Universitaire de Ressources Biologiques, Caen, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Haelewyn
authors.forename: Hélène N
authors.initials: HN
authors.lastname: David
authors.forename: Nathalie
authors.initials: N
authors.lastname: Colloc'h
authors.forename: Denis G
authors.initials: DG
authors.lastname: Colomb
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Risso
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Abraini
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects; D004195:Disease Models, Animal; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology; D009609:Nitrous Oxide / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy*; D013923:Thromboembolism / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014978:Xenon / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D014978:Xenon; D016202:N-Methylaspartate; D007530:Isoflurane; D010959:Tissue Plasminogen Activator; D009609:Nitrous Oxide