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The Role of Tryptophan Catabolism along the Kynurenine Pathway in Acute Ischemic Stroke

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Abstract

Post-stroke inflammation may induce upregulation of the kynurenine (KYN) pathway for tryptophan (TRP) oxidation, resulting in neuroprotective (kynurenic acid, KA) and neurotoxic metabolites (3-hydroxyanthranillic acid, 3-HAA). We investigated whether activity of the kynurenine pathway in acute ischemic stroke is related to initial stroke severity, long-term stroke outcome and the ischemia-induced inflammatory response. Plasma concentrations of TRP and its metabolites were measured in 149 stroke patients at admission, at 24 h, at 72 h and at day 7 after stroke onset. We evaluated the relation between the KYN/TRP ratio, the KA/3-HAA ratio and stroke severity, outcome and inflammatory parameters (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and neutrophil/lymphocyte ratio (NLR)). KYN/TRP but not KA/3-HAA correlated with the NIHSS score and with the infarct volume. Patients with poor outcome had higher mean KYN/TRP ratios than patients with more favourable outcome. The KYN/TRP ratio at admission correlated with CRP levels, ESR and NLR. The activity of the kynurenine pathway for tryptophan degradation in acute ischemic stroke correlates with stroke severity and long-term stroke outcome. Tryptophan oxidation is related to the stroke-induced inflammatory response.

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Abbreviations

3-HAA:

3-hydroxyanthranilic acid

3-OH-KYN:

3-hydroxykynurenine

CRP:

C-reactive protein

CT:

Computed tomography

ESR:

Erythrocyte sedimentation rate

IDO:

Indolamine 2,3-dioxygenase

KA:

Kynurenic acid

KYN:

Kynurenine

MRI:

Magnetic resonance imaging

NIHSS:

National Institutes of Health Stroke Scale

NMDA:

N-methyl-D-aspartic acid

NLR:

neutrophil/lymphocyte ratio

QA:

Quinolinic acid

TIA:

Transient ischemic attack

TRP:

Tryptophan

References

  1. Brouns R, De Deyn PP (2009) The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg 111:483–495

    Article  CAS  PubMed  Google Scholar 

  2. Croonenberghs J, Spaas K, Wauters A et al (2008) Faulty serotonin–DHEA interactions in autism: results of the 5-hydroxytryptophan challenge test. Neuro Endocrinol Lett 29:385–390

    PubMed  Google Scholar 

  3. Myint AM, Kim YK, Verkerk R et al (2007) Tryptophan breakdown pathway in bipolar mania. J Affect Disord 102:65–72

    Article  CAS  PubMed  Google Scholar 

  4. Van Gool AR, Verkerk R, Fekkes D et al (2008) Neurotoxic and neuroprotective metabolites of kynurenine in patients with renal cell carcinoma treated with interferon-alpha: course and relationship with psychiatric status. Psychiatry Clin Neurosci 62:597–602

    Article  PubMed  CAS  Google Scholar 

  5. Wichers MC, Koek GH, Robaeys G et al (2005) IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 10:538–544

    Article  CAS  PubMed  Google Scholar 

  6. Bonaccorso S, Marino V, Puzella A et al (2002) Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 22:86–90

    Article  CAS  PubMed  Google Scholar 

  7. Song C, Lin A, Bonaccorso S et al (1998) The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord 49:211–219

    Article  CAS  PubMed  Google Scholar 

  8. Maes M, Verkerk R, Vandoolaeghe E et al (1997) Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response. Eur Arch Psychiatry Clin Neurosci 247:154–161

    Article  CAS  PubMed  Google Scholar 

  9. Myint AM, Kim YK, Verkerk R et al (2007) Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 98:143–151

    Article  CAS  PubMed  Google Scholar 

  10. Stone TW, Mackay GM, Forrest CM et al (2003) Tryptophan metabolites and brain disorders. Clin Chem Lab Med 41:852–859

    Article  CAS  PubMed  Google Scholar 

  11. Taguchi A, Hara A, Saito K et al (2008) Localization and spatiotemporal expression of IDO following transient forebrain ischemia in gerbils. Brain Res 1217:78–85

    Article  CAS  PubMed  Google Scholar 

  12. Cozzi A, Carpenedo R, Moroni F (1999) Kynurenine hydroxylase inhibitors reduce ischemic brain damage: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3, 4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61–8048) in models of focal or global brain ischemia. J Cereb Blood Flow Metab 19:771–777

    Article  CAS  PubMed  Google Scholar 

  13. Darlington LG, Mackay GM, Forrest CM et al (2007) Altered kynurenine metabolism correlates with infarct volume in stroke. Eur J Neurosci 26:2211–2221

    Article  CAS  PubMed  Google Scholar 

  14. Bender DA, McCreanor GM (1985) Kynurenine hydroxylase: a potential rate-limiting enzyme in tryptophan metabolism. Biochem Soc Trans 13:441–443

    CAS  PubMed  Google Scholar 

  15. Alberati-Giani D, Cesura AM (1998) Expression of the kynurenine enzymes in macrophages and microglial cells: regulation by immune modulators. Amino Acids 14:251–255

    Article  CAS  PubMed  Google Scholar 

  16. Swartz KJ, During MJ, Freese A, Beal MF (1990) Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors. J Neurosci 10:2965–2973

    CAS  PubMed  Google Scholar 

  17. Okuda S, Nishiyama N, Saito H, Katsuki H (1998) 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem 70:299–307

    Article  CAS  PubMed  Google Scholar 

  18. Stone TW, Perkins MN (1981) Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 72:411–412

    Article  CAS  PubMed  Google Scholar 

  19. Taylor MW, Feng GS (1991) Relationship between interferon-gamma, indoleamine 2, 3-dioxygenase, and tryptophan catabolism. FASEB J 5:2516–2522

    CAS  PubMed  Google Scholar 

  20. Fukui S, Schwarcz R, Rapoport SI et al (1991) Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem 56:2007–2017

    Article  CAS  PubMed  Google Scholar 

  21. Brouns R, Sheorajpanday R, Wauters A et al (2008) Evaluation of lactate as a marker of metabolic stress and cause of secondary damage in acute ischemic stroke or TIA. Clin Chim Acta 397:27–31

    Article  CAS  PubMed  Google Scholar 

  22. Brouns R, Heylen E, Sheorajpanday R et al (2009) Carboxypeptidase U (TAFIa) decreases the efficacy of thrombolytic therapy in ischemic stroke patients. Clin Neurol Neurosurg 111:165–170

    Article  PubMed  Google Scholar 

  23. Brouns R, Sheorajpanday R, Kunnen J et al (2009) Clinical, biochemical and neuroimaging parameters after thrombolytic therapy predict long-term stroke outcome. Eur Neurol 62:9–15

    Article  PubMed  Google Scholar 

  24. Brouns R, Marescau B, Possemiers I et al (2009) Dimethylarginine levels in cerebrospinal fluid of hyperacute ischemic stroke patients are associated with stroke severity. Neurochem Res 34:1642–1649

    Article  CAS  PubMed  Google Scholar 

  25. Brouns R, Van Den Bossche J, De Surgeloose D et al (2009) Clinical and biochemical diagnosis of small-vessel disease in acute ischemic stroke. J Neurol Sci 285:185–190

    Article  CAS  PubMed  Google Scholar 

  26. Brouns R, Heylen E, Willemse JL et al (2010) The decrease in procarboxypeptidase U (TAFI) concentration in acute ischemic stroke correlates with stroke severity, evolution and outcome. J Thromb Haemost 8:75–80

    Article  CAS  PubMed  Google Scholar 

  27. Schroecksnadel K, Fiegl M, Prassl K et al (2007) Diminished quality of life in patients with cancer correlates with tryptophan degradation. J Cancer Res Clin Oncol 133:477–485

    Article  CAS  PubMed  Google Scholar 

  28. Pawlak K, Brzosko S, Mysliwiec M, Pawlak D (2009) Kynurenine, quinolinic acid-The new factors linked to carotid atherosclerosis in patients with end-stage renal disease. Atherosclerosis 204:561–566

    Article  CAS  PubMed  Google Scholar 

  29. Logters TT, Laryea MD, Altrichter J et al. (2008) Increased plasma kynurenine values and kynurenine: tryptophan ratios after major trauma are early indicators for the development of sepsis. Shock (in press)

  30. Heyes MP, Saito K, Devinsky O, Nadi NS (1994) Kynurenine pathway metabolites in cerebrospinal fluid and serum in complex partial seizures. Epilepsia 35:251–257

    Article  CAS  PubMed  Google Scholar 

  31. Sulter G, Steen C, De Keyser J (1999) Use of the Barthel index and modified Rankin scale in acute stroke trials. Stroke 30:1538–1541

    CAS  PubMed  Google Scholar 

  32. Dziedzic T (2008) Clinical significance of acute phase reaction in stroke patients. Front Biosci 13:2922–2927

    Article  CAS  PubMed  Google Scholar 

  33. Forrest CM, Mackay GM, Stoy N et al (2004) Tryptophan loading induces oxidative stress. Free Radic Res 38:1167–1171

    Article  CAS  PubMed  Google Scholar 

  34. Herve C, Beyne P, Jamault H, Delacoux E (1996) Determination of tryptophan and its kynurenine pathway metabolites in human serum by high-performance liquid chromatography with simultaneous ultraviolet and fluorimetric detection. J Chromatogr B Biomed Appl 675:157–161

    Article  CAS  PubMed  Google Scholar 

  35. Pawlak D, Pawlak K, Malyszko J et al (2001) Accumulation of toxic products degradation of kynurenine in hemodialyzed patients. Int Urol Nephrol 33:399–404

    Article  CAS  PubMed  Google Scholar 

  36. Mackay GM, Forrest CM, Stoy N et al (2006) Tryptophan metabolism and oxidative stress in patients with chronic brain injury. Eur J Neurol 13:30–42

    Article  CAS  PubMed  Google Scholar 

  37. McMillan DC (2009) Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 12:223–226

    Article  PubMed  Google Scholar 

  38. Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1:609–620

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Raf Brouns was a research assistant of the Fund for Scientific research Flanders (FWO-Vlaanderen). This research was also supported by the Institute Born-Bunge; the agreement between the Institute Born-Bunge and the University of Antwerp; the Interuniversity Attraction Poles (IAP) program P6/43 of the Belgian Federal Science Policy Office, Belgium; and the Medical Research Foundation Antwerp.

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Authors and Affiliations

  1. Department of Neurology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium

    Raf Brouns

  2. Laboratory for Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium

    Raf Brouns, Tony Aerts & Peter P. De Deyn

  3. Department of Neurology and Memory Clinic, ZNA Middelheim Hospital, Antwerp, Belgium

    Raf Brouns & Peter P. De Deyn

  4. Laboratory for Medical Biochemistry, University of Antwerp, Antwerp, Belgium

    Robert Verkerk & Simon Scharpé

  5. Department of Radiology, ZNA Middelheim Hospital, Antwerp, Belgium

    Didier De Surgeloose

  6. Department of Clinical Biology, ZNA Middelheim Hospital, Antwerp, Belgium

    Annick Wauters

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  1. Raf Brouns
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  2. Robert Verkerk
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  7. Peter P. De Deyn
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Correspondence to Peter P. De Deyn.

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Brouns, R., Verkerk, R., Aerts, T. et al. The Role of Tryptophan Catabolism along the Kynurenine Pathway in Acute Ischemic Stroke. Neurochem Res 35, 1315–1322 (2010). https://doi.org/10.1007/s11064-010-0187-2

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  • DOI: https://doi.org/10.1007/s11064-010-0187-2

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