Stress-related regulation of the kynurenine pathway: Relevance to neuropsychiatric and degenerative disorders

Abstract

The kynurenine pathway (KP), which is activated in times of stress and infection has been implicated in the pathophysiology of neurodegenerative and psychiatric disorders. Activation of this tryptophan metabolising pathway results in the production of neuroactive metabolites which have the potential to interfere with normal neuronal functioning which may contribute to altered neuronal transmission and the emergence of symptoms of these brain disorders. This review investigates the involvement of the KP in a range of neurological disorders, examining recent in vitro, in vivo and clinical discoveries highlights evidence to indicate that the KP is a potential therapeutic target in both neurodegenerative and stress-related neuropsychiatric disorders. Furthermore, this review identifies gaps in our knowledge with regard to this field which are yet to be examined to lead to a more comprehensive understanding of the role of KP activation in brain health and disease. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.

Glial and tissue-specific regulation of Kynurenine Pathway dioxygenases by acute stress of mice

“…The relevance of these findings to human well-being remains conjectural. The Kynurenine Pathway is implicated in mediating symptoms of depression induced by chronic stress and inflammation ( O'Farrell and Harkin, 2015 ). Increased plasma Kyn and cerebral spinal fluid levels of Kyn and QuinA are associated with depression symptomology in patients treated with IFNα ( Raison et al., 2010 ).…”

“…Nearly half of Americans report experiencing at least one psychiatric disorder at some point in their lives, the most common being depression ( Kessler et al., 2003 , Kessler et al., 1994 ). Mounting evidence supports a causal link between stress-induced activation of the Kynurenine Pathway and psychiatric disorders, including depression ( Myint et al., 2012 , O'Farrell and Harkin, 2015 , Won and Kim, 2015 ) and schizophrenia ( Chiappelli et al., 2014 , Pocivavsek et al., 2016 ). Stress can also trigger depression, as well as influence the length and severity of depressive episodes ( Gold et al., 2015 ).…”

The kynurenine pathway and the brain: Challenges, controversies and promises

“…In principle, early developmental impairments may be genetic in origin or caused by adverse external influences including bacterial or viral infections, exposure to environmental or dietary toxins, or experience of stressful situations (O’Farrell and Harkin, 2016). It is now recognised that these factors directly affect the kynurenine pathway in at least three general ways.…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Whether α7 receptor nicotinic receptor agonists should be considered exclusively in patients with high inflammation and anhedonia and/or cognitive dysfunction remains an open question worthy of further exploration. It should also be noted that the neuroprotective effects of kynurenic acid have been well established in neurodegenerative disorders (O'Farrell and Harkin, 2015), and therefore drugs that block kynurenic acid (as opposed to stimulating the α7 receptor nicotinic receptor) should be considered with caution.…”