Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later

Abstract

The original 1969 Lancet paper proposed in depression the activity of liver tryptophan-pyrrolase is stimulated by raised blood corticosteroids levels, and metabolism of tryptophan is shunted away from serotonin production, and towards kynurenine production. Discovery of neurotropic activity of kynurenines suggested that up-regulation of the tryptophan-kynurenine pathway not only augmented serotonin deficiency but also underlined depression-associated anxiety, psychosis and cognitive decline. The present review of genetic and hormonal factors regulating kynurenine pathway of tryptophan metabolism suggests that this pathway mediates both genetic and environmental mechanisms of depression. Rate-limiting enzymes of kynurenine formation, tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are activated by stress hormones (TDO) and/or by pro-inflammatory cytokines (IDO). Simultaneous presence of high producers alleles of proinflammatory cytokines genes (e.g., interferon-gamma and tumor necrosis factor-alpha) determines the genetic predisposition to depression via up-regulation of IDO while impact of environmental stresses is mediated via hormonal activation of TDO. Tryptophan-kynurenine pathway represents a major meeting point of gene-environment interaction in depression and a new target for pharmacological intervention.

Figure 1

Shunt of TRY metabolism from 5-HT to KYN production in depression (1) Abbreviations: TRY – tryptophan; 5-HT – serotonin; TDO – tryptophan 2,3-dioxygenase

Figure 2

Methoxyindoles and kynurenine pathways of tryptophan metabolism Abbreviations: TRY – tryptophan; IDO – indoleamine 2,3-dioxygenase; TDO- tryptophan 2,3-dioxygenase; TPH – tryptophan hydroxylase; 5-HT – serotonin; NAT – N-acetyltransferase; NAS – N-acetylserotonin; NAD - nicotinamide adenine dinucleotide

Figure 3

Kynurenines and psychiatric and vascular complications Abbreviations: TRY – tryptophan; IDO – indoleamine 2,3-dioxygenase; TDO – tryptophan 2,3-dioxygenase; BBB – blood brain barrier; KYN - kynurenine, 3HKYN - 3-hydroxyKYN; KYNA – kynurenic acid; QUIN – quinolinic acid; iNOS – inducible nitric oxide synthase; NO - nitric oxide; PLA – phospholipase; AA – arachidonic acid; COX - cycloxygenase; 5-LO - arachidonate 5-lipoxygenase; PGE – prostaglandines.

Figure 4

Cytokines and regulation of IDO Abbreviations: IFNG – interferone-gamma; IFN-alpha – interferone-alpha; TNF-alpha – tumor necrosis factor-alpha; IDO – indoleamine 2, 3-oxygenase

Figure 5

Genetic and environmental impacts on tryptophan metabolism Abbreviations: NAS – N-acetylserotonin; IFNG – interferone; TNF – tumor necrosis factor; IDO – indoleamine 2,3-dioxygenase; TDO – tryptophan 2,3-dioxygenase.