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

被引:69
|
作者
Clark, Sarah M. [1 ]
Pocivavsek, Ana [2 ]
Nicholson, James D. [1 ]
Notarangelo, Francesca M. [2 ]
Langenberg, Patricia [3 ]
McMahon, Robert P. [2 ]
Kleinman, Joel E. [4 ,5 ]
Hyde, Thomas M. [4 ,5 ]
Stiller, John [6 ]
Postolache, Teodor T. [6 ]
Schwarcz, Robert [2 ]
Tonelli, Leonardo H. [1 ]
机构
[1] Univ Maryland, Sch Med, Dept Psychiat, Lab Behav Neuroimmunol, 655 W Baltimore St, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, 655 W Baltimore St, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 655 W Baltimore St, Baltimore, MD 21201 USA
[4] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Div Intramural Res Programs,NIH, Bethesda, MD 20892 USA
[5] Lieber Inst Brain Dev, Johns Hopkins Med Campus, Baltimore, MD USA
[6] Univ Maryland, Sch Med, Dept Psychiat, Mood & Anxiety Program, 655 W Baltimore St, Baltimore, MD 21201 USA
来源
JOURNAL OF PSYCHIATRY & NEUROSCIENCE | 2016年 / 41卷 / 06期
关键词
ACUTE TRYPTOPHAN DEPLETION; NECROSIS-FACTOR-ALPHA; REAL-TIME PCR; INTERFERON-ALPHA; QUINOLINIC ACID; ADOLESCENT DEPRESSION; ORBITOFRONTAL CORTEX; MAJOR DEPRESSION; BIPOLAR DISORDER; SUICIDE VICTIMS;
D O I
10.1503/jpn.150226
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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- and tumour necrosis factor-. 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.
引用
收藏
页码:386 / 394
页数:9
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