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A combination of untargeted and targeted metabolomics approaches unveils changes in the kynurenine pathway following cardiopulmonary resuscitation

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Abstract

The mechanisms responsible for post-resuscitation myocardial and cerebral dysfunction are not well understood, especially in the early post-resuscitation phases. In this investigation, we first adopted unbiased mass spectrometry-based metabolomic profiling to identify perturbations in circulating metabolites in a rat model of cardiac arrest and cardiopulmonary resuscitation. Our findings strongly indicated early alterations in a major route of the tryptophan catabolism, namely the kynurenines pathway, after resuscitation. Specific metabolites involved in the tryptophan catabolism were quantified absolutely using liquid chromatography-multiple reaction monitoring-mass spectrometry. Tryptophan plasma concentration fell significantly very early in the post-resuscitation phase, while its metabolites, l-kynurenine, kynurenic acid, 3-hydroxyanthranilic acid and 5-hydroxyindoleacetic acid, rose significantly. Changes in their concentration reflected changes in rat post-resuscitation myocardial dysfunction. Elevated plasma level of kynurenic acid, 3-hydroxyanthranilic acid were associated with significant decrease in ejection fraction and stroke volume. It is well known that kynurenines pathway is involved in the pathogenesis of numerous central nervous system disorders. By implication, altered levels of tryptophan metabolites in the early post resuscitation phase might contribute to the degree of cognitive recovery. Our results suggest that kynurenine pathway is activated early following resuscitation from cardiac arrest and might account for the severity of post-resuscitation syndrome. Our explorative investigation indicate that metabolomics can help to clarify unexplored biochemical pathways in cardiopulmonary resuscitation.

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Abbreviations

3-HAA:

3-Hydroxyanthranilic acid

5-HAA:

5-Hydroxyanthranilic acid

5-HIAA:

5-Hydroxyindoleacetic acid

CA:

Cardiac arrest

CPR:

Cardiopulmonary resuscitation

FFA:

Free fatty acids

IDO:

Indoleamine-2,3-dioxygenase

KYN:

l-kynurenine

KYNA:

Kynurenic acid

S1P:

Sphingosine 1 phosphate

TRP:

Tryptophan

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Acknowledgments

We thank J.D. Baggott for help in preparing the manuscript. GR is currently recipient of an “Amiche del Mario Negri” fellowship.

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Authors and Affiliations

  1. Gene and Protein Biomarkers Unit, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milano, Italy

    Laura Brunelli & Roberta Pastorelli

  2. Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy

    Giuseppe Ristagno, Francesca Fumagalli & Roberto Latini

  3. Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milano, Italy

    Renzo Bagnati & Roberto Fanelli

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  1. Laura Brunelli
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Correspondence to Roberta Pastorelli.

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Brunelli, L., Ristagno, G., Bagnati, R. et al. A combination of untargeted and targeted metabolomics approaches unveils changes in the kynurenine pathway following cardiopulmonary resuscitation. Metabolomics 9, 839–852 (2013). https://doi.org/10.1007/s11306-013-0506-0

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