Psychoneuroimmunology: Where kynurenic acid fits

Psychoneuroimmunology. It’s a mouthful, but that’s to be expected when trying to find one word to describe the interaction of the nervous, endocrine, and immune systems and the impact this has on health and disease. Robert Ader, considered the founding father of this emerging medical paradigm, coined the term in the late 1970s. The role of the immune system in influencing behaviors is one of the most intriguing concepts in medical research as well as clinical practice. An upregulated immune system has significant effects on the tryptophan pathway, including increasing the level of kynurenic acid, and those effects lead to depressive-like behavior.

Figure 1.  The activated IDO enzyme shunts tryptophan dow the kynurenine pathway to kynurenic acid as well as increasing serotonin breakdown leading to depressive-like behavior.  Adapted from Corona 2013.

Figure 1. The activated IDO enzyme shunts tryptophan dow the kynurenine pathway to kynurenic acid as well as increasing serotonin breakdown leading to depressive-like behavior. Adapted from Corona 2013.

Indoleamine 2,3-dioxygenase (IDO) is an enzyme present in microglial cells of the nervous system. This enzyme, turned on by pro-inflammatory mediators, is responsible for the “tryptophan steal.” Inflammation activates microglia to release this enzyme. Once activated, IDO shunts the serotonin precursor tryptophan down the kynurenine pathway (Figure 1). This increases the ratio of kynurenine:tryptophan and may decrease serotonin synthesis.

IDO also metabolizes 5-hydroxytryptophan (5-HTP) as well as serotonin into 5-hydroxykynuramine. This means in the presence of immune activation, serotonin turnover is increased. This is characterized by a greater 5-HIAA:serotonin ratio. In fact, after administering an IDO inhibitor to mice whose immune systems were upregulated, depressive-like behavior lessened and there were also decreased ratios of 5-HIAA:serotonin and kynurenine:tryptophan.

A rapidly growing body of evidence supports the fact that inflammation has a notable effect on behaviors. More advanced tools, such as kynurenic acid, to assess the impact of inflammation on nervous system function will help manage behavioral disorders whose mechanism is rooted in immune modulation. This is psychoneuroimmunology in motion.

References:
Ader, R. (2007) Psychoneuroimmunology. Burlington, MA: Elsevier Academic Press.
Corona AW, Norden DM, Skendelas JP, et al. (2013). Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice. Brain Behav Immun, 31:134-42.
http://www.journals.elsevier.com/brain-behavior-and-immunity/
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