title: Modulation by the Noble Gas Helium of Tissue Plasminogen Activator: Effects in a Rat Model of Thromboembolic Stroke.
abstract: Helium has been shown to provide neuroprotection in mechanical model of acute ischemic stroke by inducing hypothermia, a condition shown by itself to reduce the thrombolytic and proteolytic properties of tissue plasminogen activator. However, whether or not helium interacts with the thrombolytic drug tissue plasminogen activator, the only approved therapy of acute ischemic stroke still remains unknown. This point is not trivial since previous data have shown the critical importance of the time at which the neuroprotective noble gases xenon and argon should be administered, during or after ischemia, in order not to block tissue plasminogen activator-induced thrombolysis and to obtain neuroprotection and inhibition of tissue plasminogen activator-induced brain hemorrhages.
  
  
  
  We show that helium of 25-75 vol% inhibits in a concentration-dependent fashion the catalytic and thrombolytic activity of tissue plasminogen activator in vitro and ex vivo. In vivo, in rats subjected to thromboembolic brain ischemia, we found that intraischemic helium at 75 vol% inhibits tissue plasminogen activator-induced thrombolysis and subsequent reduction of ischemic brain damage and that postischemic helium at 75 vol% reduces ischemic brain damage and brain hemorrhages.
  
  
  
  In a clinical perspective for the treatment of acute ischemic stroke, these data suggest that helium 1) should not be administered before or together with tissue plasminogen activator therapy due to the risk of inhibiting the benefit of tissue plasminogen activator-induced thrombolysis; and 2) could be an efficient neuroprotective agent if given after tissue plasminogen activator-induced reperfusion.
authors.affiliation: 1Université de Caen Normandie, CURB, Normandie-Université, Caen, France. 2Département d'Anesthésiologie, Université Laval, Québec, QC, Canada. 3Institut de Recherche Biomédicale des Armées, Équipe Résidente de Recherche Subaquatique Opérationnelle, France. 4Université de Caen Normandie, Faculté de Médecine, Normandie-Université, Caen, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Haelewyn
authors.forename: Hélène N
authors.initials: HN
authors.lastname: David
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Blatteau
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vallée
authors.forename: Cedric
authors.initials: C
authors.lastname: Meckler
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Risso
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Abraini
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006371:Helium / Q000008:administration & dosage* / Q000494:pharmacology; D020300:Intracranial Hemorrhages / Q000188:drug therapy; D008297:Male; D051381:Rats; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D013923:Thromboembolism / Q000150:complications / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*
chemical_list: D000933:Antifibrinolytic Agents; D006371:Helium; D010959:Tissue Plasminogen Activator