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

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

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J Psychiatry Neurosci 2016;41(6):386-394

Sarah M. Clark, PhD*; Ana Pocivavsek, PhD*; James D. Nicholson, PhD; Francesca M. Notarangelo, PhD; Patricia Langenberg, PhD; Robert P. McMahon, PhD; Joel E. Kleinman, MD, PhD; Thomas M. Hyde, MD, PhD; John Stiller, MD; Teodor T. Postolache, MD; Robert Schwarcz, PhD; Leonardo H. Tonelli, PhD

Abstract

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.


*These authors contributed equally to this work.

Submitted June 19, 2015; Revised Dec. 16, 2015; Accepted Dec. 18, 2015; Early-released Apr. 12, 2016

Acknowledgements: This study was supported in part by grants from the National Institute of Mental Health (MH097676 to L.H.T. and MH083729 to R.S.). Ryan Mulford and Partam Manalai are acknowledged for their technical assistance with tissue processing and mRNA purification.

Affiliations: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).

Competing interests: R. Schwarcz reports equity from Vistagen outside the submitted work. He also holds a patent “Small Inhibitors of Kynurenine 3-Monooxygenase” and has a patent “A new class of 3-hydroxyanthranilate-3,4-dioxygenase (3-HAO) inhibitors as potential neuroprotective drugs” pending. L. Tonelli is supported by a grant from the National Institute of Health. No other competing interests declared.

Contributors: T. Postolache, R. Schwarcz, J. Stiller and L. Tonelli designed the study. S. Clark, A. Pocivavsek, J. Nicholson, F. Notarangelo, P. Langenberg, J. Kleinman, T. Hyde, R. Schwarcz and L. Tonelli acquired the data, which S. Clark, A. Pocivavsek, J. Nicholson, F. Notarangelo, P. Langenberg, R. McMahon, T. Postolache, R. Schwarcz and L. Tonelli analyzed. S. Clark, A. Pocivavsek, R. McMahon, T. Postolache, R. Schwarcz and L. Tonelli wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.150226

Correspondence to: L.H. Tonelli, Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, 655 W. Baltimore St. Baltimore MD, 21201, USA; ltonelli@psych.umaryland.edu