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Role of the Kynurenine Pathway in Stroke

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Book cover Targeting the Broadly Pathogenic Kynurenine Pathway

Abstract

Stroke is the second and fifth leading cause of death for people aged >60 and 15–59 years, respectively. Many stroke survivors suffer from chronic health problems that necessitate a long-term process of recovery and rehabilitation. There is increasing evidence that inflammation plays an important role in acute ischemic stroke (AIS), indicating the presence of important interactions between the nervous and immune systems. Furthermore, there are currently strong indications for a close relationship between the immune system and indoleamine-2,3-dioxygenase (IDO)-induced tryptophan catabolism [the kynurenine (KYN) pathway]. Although KYN pathway metabolites can produce excitatory and oxidative neurotoxicity, they can also protect neurons from inflammatory damage and attenuate excitatory neurotoxicity via N-methyl-d-aspartate receptor antagonism. Thus, activation of IDO in the central nervous system might be a double-edged sword. Recent studies indicate that the KYN pathway is activated immediately after a stroke, that this is related to the stroke-induced inflammatory response, and also that this IDO-induced tryptophan catabolism is correlated with a worse outcome. Since activation of the KYN pathway may disturb brain serotonin (5-hydroxytryptamine) and glutamate neurotransmission, it is reasonable to assume that inflammation-induced IDO activity in AIS is involved in several sequelae following stroke, such as cognitive impairment, depression, and fatigue. Many AIS survivors suffer from post-stroke fatigue and post-stroke depression, indicating the importance of increasing the base of knowledge about the mechanisms underlying these sequelae. In this chapter, we present and discuss findings that support the notion that the AIS-induced immune response and IDO activation are related to post-stroke fatigue but not to post-stroke depression.

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Abbreviations

3-HK:

3-Hydroxykynurenine

AIS:

Acute ischemic stroke

CRP:

C-reactive protein

CSF:

Cerebrospinal fluid

hsCRP:

High-sensitivity C-reactive protein

IDO:

Indoleamine 2,3-dioxygenase

IL:

Interleukin

KA:

Kynurenic acid

KATs:

Kynurenine aminotransferases

KYN:

Kynurenine

NIHSS:

National Institutes of Health Stroke Scale

NMDA:

N-methyl-d-aspartate

PSD:

Post-stroke depression

PSF:

Post-stroke fatigue

QA:

Quinolinic acid

SAR:

Superoxide anion radical

TDO:

Tryptophan 2,3-dioxygenase

TNF-α:

Tumor necrosis factor-α

TRP:

Tryptophan

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Authors and Affiliations

  1. Faculty of Health Sciences, Buskerud and Vestfold University College, 3004, Drammen, Norway

    Heidi Ormstad Ph.D.

  2. Laboratory of Medical Biochemistry, University of Antwerp, Antwerp, Belgium

    Robert Verkerk Ing.

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  1. Heidi Ormstad Ph.D.
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  2. Robert Verkerk Ing.
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Correspondence to Heidi Ormstad Ph.D. .

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  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

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Ormstad, H., Verkerk, R. (2015). Role of the Kynurenine Pathway in Stroke. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_17

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