title: Early kynurenine pathway activation following cardiac arrest in rats, pigs, and humans.
abstract: OBJECTIVE
  Kynurenine pathway (KP) is a major route of the tryptophan (TRP) catabolism. In the present study, TRP and KP metabolites concentrations were measured in plasma from rats, pigs and humans after cardiac arrest (CA) in order to assess KP activation and its potential role in post-resuscitation outcome.
  
  
  METHODS
  Plasma was obtained from: (A) 24 rats, subjected to 6 min CA and 6 min of cardiopulmonary resuscitation (CPR); (B) 10 pigs, subjected to 10 min CA and 5 min CPR; and (C) 3 healthy human volunteers and 5 patients resuscitated from CA. KP metabolites were quantified by liquid chromatography multiple reaction monitoring mass spectrometry. Assessments were available at baseline, and 1-4h, and 3-5 days post-CA.
  
  
  RESULTS
  KP was activated after CA in rats, pigs, and humans. Decreases in TRP occurred during the post-resuscitation period and were accompanied by significant increases in its major metabolites, 3-hydroxyanthranilic acid (3-HAA) and kynurenic acid in each species, that persisted up to 3-5 days post-CA (p<0.01). In rats, changes in KP metabolites reflected changes in post-resuscitation myocardial function. In pigs, changes in TRP and increases in 3-HAA were significanlty related to the severity of cerebral histopathogical injuries. In humans, KP activation was observed, together with systemic inflammation. Post-CA increases in 3-HAA were greater in patients that did not survive.
  
  
  CONCLUSIONS
  In this fully translational investigation, the KP was activated early following resuscitation from CA in rats, pigs, and humans, and might have contributed to post-resuscitation outcome.
authors.affiliation: Department of Cardiovascular Research, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy. Electronic address: gristag@gmail.com.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ristagno
authors.forename: Michael
authors.initials: M
authors.lastname: Fries
authors.forename: Laura
authors.initials: L
authors.lastname: Brunelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Fumagalli
authors.forename: Renzo
authors.initials: R
authors.lastname: Bagnati
authors.forename: Ilaria
authors.initials: I
authors.lastname: Russo
authors.forename: Lidia
authors.initials: L
authors.lastname: Staszewsky
authors.forename: Serge
authors.initials: S
authors.lastname: Masson
authors.forename: Giovanni
authors.initials: G
authors.lastname: Li Volti
authors.forename: Agata
authors.initials: A
authors.lastname: Zappalà
authors.forename: Matthias
authors.initials: M
authors.lastname: Derwall
authors.forename: Anne
authors.initials: A
authors.lastname: Brücken
authors.forename: Roberta
authors.initials: R
authors.lastname: Pastorelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Latini
mesh_terms: D000818:Animals; D016887:Cardiopulmonary Resuscitation; D002853:Chromatography, Liquid; D006323:Heart Arrest / Q000378:metabolism* / Q000628:therapy; D006439:Hemodynamics; D006801:Humans; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D013552:Swine
chemical_list: D007737:Kynurenine
keywords: Brain injury; Cardiac arrest; Kynurenine pathway; Outcome; Post cardiac arrest syndrome; Tryptophan