Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

Background Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive meta...

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Published in:Journal of psychiatry & neuroscience 2016-11, Vol.41 (6), p.386-394
Main Authors: Clark, Sarah M., PhD, Pocivavsek, Ana, PhD, Nicholson, James D., PhD, Notarangelo, Francesca M., PhD, Langenberg, Patricia, PhD, McMahon, Robert P., PhD, Kleinman, Joel E., MD, PhD, Hyde, Thomas M., MD, PhD, Stiller, John, MD, Postolache, Teodor T., MD, Schwarcz, Robert, PhD, Tonelli, Leonardo H., PhD
Format: Article
Language:English
Subjects:
Adult
Antidepressants
Chromatography
Cytokines
Cytokines - metabolism
Depression, Mental
Depressive Disorder - drug therapy
Depressive Disorder - metabolism
Depressive Disorder - pathology
Female
Gene expression
Health aspects
Humans
Hypotheses
Illnesses
Immune system
Immunohistochemistry
Immunotherapy
Kynurenine - metabolism
Male
Medical Education
Mental depression
Metabolism
Metabolites
Physiological aspects
Polymerase Chain Reaction
Prefrontal cortex
Prefrontal Cortex - metabolism
Prefrontal Cortex - pathology
Psychiatry
Research Paper
RNA, Messenger - metabolism
Studies
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Summary:Background Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology. Methods We used postmortem brain tissue from the ventrolateral prefrontal cortex (VLPFC) to assess tissue levels of tryptophan and KP metabolites, the expression of several KP enzymes and a series of cytokines as well as tissue pathology, including microglial activation. Tissue samples came from nonpsychiatric controls ( n = 36) and individuals with depressive disorder not otherwise specified (DD-NOS, n = 45) who died of natural causes, homicide, accident, or suicide. Results We found a reduction in the enzymatic conversion of tryptophan to kynurenine, determined using the kynurenine:tryptophan ratio, and reduced messenger RNA expression of the enzymes indoleamine-2,3-dioxygenase 1 and 2 and tryptophan-2,3-dioxygenase in depressed individuals irrespective of the cause of death. These findings correlated with reductions in the expression of several cytokines, including interferon-γ and tumour necrosis factor-α. Notably, quinolinic acid levels were also lower in depressed individuals than controls. Limitations Information on the use of antidepressants and other psychotropic medications was insufficient for statistical comparisons. Conclusion Contrary to expectations, the present results indicate that depression, in the absence of medical illness or an overt inflammatory process, is associated with compromised, rather than increased, KP metabolism in the VLPFC.
ISSN:1180-4882
1488-2434
DOI:10.1503/jpn.150226