Journal of Molecular Neuroscience

, Volume 54, Issue 2, pp 181–187 | Cite as

Activation of the Kynurenine Pathway in the Acute Phase of Stroke and its Role in Fatigue and Depression Following Stroke

  • Heidi Ormstad
  • Robert Verkerk
  • Karl-Friedrich Amthor
  • Leiv Sandvik
Article

Abstract

Many stroke survivors suffer from poststroke fatigue (PSF) and poststroke depression (PSD), indicating the importance of increasing the base of knowledge about the mechanisms underlying these sequelae. The primary aim of this study was to determine whether activation of the kynurenine (KYN) pathway predicts subsequent fatigue or depression in acute ischemic stroke (AIS) patients. Acute serum levels of 5-hydroxytryptamine (5-HT), tryptophan (TRP) catabolites (TRYCATs), and competing amino acids, as well as subsequent fatigue and depression, were measured in 45 stroke patients. TRP index [=100 × TRP / (tyrosine + valine + phenylalanine + leucine + isoleucine)] was significantly lower in patients with a Fatigue Severity Scale (FSS) score of ≥4 at 12 months than in those with an FSS score of <4 (p = 0.039). Furthermore, the serum level of kynurenic acid in the acute stroke phase was significantly higher in patients with an FSS of score ≥4 at 18 months than in those with an FSS score of <4 (p = 0.026). These findings indicate that stroke patients with PSF have a lower bioavailability of TRP for 5-HT synthesis in the brain in the acute stroke phase. However, they also appear to have greater neuroprotective potential in that phase. In contrast to PSF, no predictors of PSD were found. These findings together with those of previous studies suggest that the immune response and indoleamine 2,3-dioxygenase activation that follows AIS can predict PSF but not PSD.

Keywords

Acute ischemic stroke Kynurenine pathway Cytokines Poststroke fatigue Poststroke depression 

References

  1. Aben I et al (2002) Validity of the beck depression inventory, hospital anxiety and depression scale, SCL-90, and hamilton depression rating scale as screening instruments for depression in stroke patients. Psychosomatics 43:386–393PubMedCrossRefGoogle Scholar
  2. Adams HP Jr et al (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41PubMedCrossRefGoogle Scholar
  3. Anderson GM et al (1987) Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 28:885–900PubMedCrossRefGoogle Scholar
  4. Anderson G, Maes M, Berk M (2012) Biological underpinnings of the commonalities in depression, somatization, and Chronic Fatigue Syndrome. Med Hypotheses 78:752–756PubMedCrossRefGoogle Scholar
  5. Ayerbe L et al (2013) Natural history, predictors and outcomes of depression after stroke: systematic review and meta-analysis. Br J Psychiatry 202:14–21PubMedCrossRefGoogle Scholar
  6. Barker-Collo S, Feigin VL, Dudley M (2007) Post stroke fatigue—where is the evidence to guide practice? N Z Med J 120:U2780PubMedGoogle Scholar
  7. Beck AT et al (1996) Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess 67:588–597PubMedCrossRefGoogle Scholar
  8. Choi-Kwon S et al (2005) Poststroke fatigue: characteristics and related factors. Cerebrovasc Dis 19:84–90PubMedCrossRefGoogle Scholar
  9. Dantzer R (2009) Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am 29:247–264PubMedCentralPubMedCrossRefGoogle Scholar
  10. Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160PubMedCentralPubMedCrossRefGoogle Scholar
  11. Duncan F, Wu S, Mead GE (2012) Frequency and natural history of fatigue after stroke: a systematic review of longitudinal studies. J Psychosom Res 73:18–27PubMedCrossRefGoogle Scholar
  12. Eilertsen G, Ormstad H, Kirkevold M (2013) Experiences of poststroke fatigue: qualitative meta-synthesis. J Adv Nurs 69:514–525PubMedCrossRefGoogle Scholar
  13. Fang J, Cheng Q (2009) Etiological mechanisms of post-stroke depression: a review. Neurol Res 31:904–909PubMedCrossRefGoogle Scholar
  14. Fernstrom JD (1983) Role of precursor availability in control of monoamine biosynthesis in brain. Physiol Rev 63:484–546PubMedGoogle Scholar
  15. Gold AB et al (2011) The relationship between indoleamine 2,3-dioxygenase activity and post-stroke cognitive impairment. J Neuroinflammation 8:17PubMedCentralPubMedCrossRefGoogle Scholar
  16. Hackett ML et al (2008) Interventions for preventing depression after stroke. Cochrane Database Syst Rev CD003689Google Scholar
  17. Heesen C et al (2006) Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry 77:34–39PubMedCentralPubMedCrossRefGoogle Scholar
  18. Herve C et al (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 675:157–161PubMedCrossRefGoogle Scholar
  19. Ingles JL, Eskes GA, Phillips SJ (1999) Fatigue after stroke. Arch Phys Med Rehabil 80:173–178PubMedCrossRefGoogle Scholar
  20. Krupp LB et al (1989) The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 46:1121–1123PubMedCrossRefGoogle Scholar
  21. Kurz K et al (2012) Fatigue in patients with lung cancer is related with accelerated tryptophan breakdown. PLoS One 7:e36956PubMedCentralPubMedCrossRefGoogle Scholar
  22. Lerdal A., et al. (2012) The course of fatigue during the first 18months after first-ever stroke: a longitudinal study. Stroke research and treatment. 2012, 126275Google Scholar
  23. Levin SG, Godukhin OV (2011) Anti-inflammatory cytokines, TGF-beta1 and IL-10, exert anti-hypoxic action and abolish posthypoxic hyperexcitability in hippocampal slice neurons: comparative aspects. Exp Neurol 232:329–332PubMedCrossRefGoogle Scholar
  24. Maes M et al (2012) Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 10:66PubMedCentralPubMedCrossRefGoogle Scholar
  25. Markus CR et al (2005) Evening intake of alpha-lactalbumin increases plasma tryptophan availability and improves morning alertness and brain measures of attention. Am J Clin Nutr 81:1026–1033PubMedGoogle Scholar
  26. McGeough E. et al. (2009) Interventions for post-stroke fatigue. Cochrane Database Syst Rev. CD007030Google Scholar
  27. Menzies V, Lyon DE (2010) Integrated review of the association of cytokines with fibromyalgia and fibromyalgia core symptoms. Biol Res Nurs 11:387–394PubMedCentralPubMedCrossRefGoogle Scholar
  28. Michael KM, Allen JK, Macko RF (2006) Fatigue after stroke: relationship to mobility, fitness, ambulatory activity, social support, and falls efficacy. Rehabil Nurs 31:210–217PubMedCrossRefGoogle Scholar
  29. Monti JM (2011) Serotonin control of sleep-wake behavior. Sleep Med Rev 15:269–281PubMedCrossRefGoogle Scholar
  30. Morris G. Maes M. (2012) A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain DisGoogle Scholar
  31. Naess H et al (2005) Fatigue at long-term follow-up in young adults with cerebral infarction. Cerebrovasc Dis 20:245–250PubMedCrossRefGoogle Scholar
  32. Naess H et al (2006) Health-related quality of life among young adults with ischemic stroke on long-term follow-up. Stroke 37:1232–1236PubMedCrossRefGoogle Scholar
  33. Ormstad H et al (2011a) Serum cytokine and glucose levels as predictors of poststroke fatigue in acute ischemic stroke patients. J Neurol 258:670–676PubMedCentralPubMedCrossRefGoogle Scholar
  34. Ormstad H et al (2011b) Serum levels of cytokines and C-reactive protein in acute ischemic stroke patients, and their relationship to stroke lateralization, type, and infarct volume. J Neurol 258:677–685PubMedCentralPubMedCrossRefGoogle Scholar
  35. Ormstad H et al (2012) Serum levels of cytokines, glucose, and hemoglobin as possible predictors of poststroke depression, and association with poststroke fatigue. Int J Neurosci 122:682–690PubMedCrossRefGoogle Scholar
  36. Ormstad H. et al. (2013) Inflammation-induced catabolism of tryptophan and tyrosine in acute ischemic stroke. J Mol NeurosciGoogle Scholar
  37. Rocha e Silva CE et al (2013) Is poststroke depression a major depression? Cerebrovasc Dis 35:385–391PubMedCrossRefGoogle Scholar
  38. Scalzo P et al (2010) Serum levels of interleukin-6 are elevated in patients with Parkinson's disease and correlate with physical performance. Neurosci Lett 468:56–58PubMedCrossRefGoogle Scholar
  39. Schepers VP et al (2006) Poststroke fatigue: course and its relation to personal and stroke-related factors. Arch Phys Med Rehabil 87:184–188PubMedCrossRefGoogle Scholar
  40. Schroecksnadel K et al (2007) Diminished quality of life in patients with cancer correlates with tryptophan degradation. J Cancer Res Clin Oncol 133:477–485PubMedCrossRefGoogle Scholar
  41. Segev-Amzaleg N, Trudler D, Frenkel D (2013) Preconditioning to mild oxidative stress mediates astroglial neuroprotection in an IL-10-dependent manner. Brain Behav Immun 30:176–185PubMedCrossRefGoogle Scholar
  42. Seruga B et al (2008) Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 8:887–899PubMedCrossRefGoogle Scholar
  43. Spalletta G et al (2006) The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines. Mol Psychiatry 11:984–991PubMedCrossRefGoogle Scholar
  44. Stoll G, Jander S, Schroeter M (2000) Cytokines in CNS disorders: neurotoxicity versus neuroprotection. J Neural Transm Suppl 59:81–89PubMedGoogle Scholar
  45. Swartz KJ et al (1990) Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors. J Neurosci 10:2965–2973PubMedGoogle Scholar
  46. Turnell DC, Cooper JD (1982) Rapid assay for amino acids in serum or urine by pre-column derivatization and reversed-phase liquid chromatography. Clin Chem 28:527–531PubMedGoogle Scholar
  47. van der Werf SP et al (2001) Experience of severe fatigue long after stroke and its relation to depressive symptoms and disease characteristics. Eur Neurol 45:28–33PubMedCrossRefGoogle Scholar
  48. Yamamoto T, Azechi H, Board M (2012) Essential role of excessive tryptophan and its neurometabolites in fatigue. Can J Neurol Sci 39:40–47PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Heidi Ormstad
    • 1
    • 2
  • Robert Verkerk
    • 3
  • Karl-Friedrich Amthor
    • 4
  • Leiv Sandvik
    • 5
  1. 1.Faculty of Health SciencesBuskerud and Vestfold University CollegeDrammenNorway
  2. 2.Vestre Viken Hospital TrustBuskerudNorway
  3. 3.Laboratory of Medical BiochemistryUniversity of AntwerpAntwerpBelgium
  4. 4.Department of NeurologyVestre Viken Hospital TrustBuskerudNorway
  5. 5.Section of BiostatisticsOslo University HospitalOsloNorway

Personalised recommendations