Home > News > Tryptophan Metabolism as a New Target for the Treatment of Schizophrenia
Psychiatric Disorders
Read Time: 2 mins

Tryptophan Metabolism as a New Target for the Treatment of Schizophrenia

Published Online: June 4th 2011
Authors: Gregory F Oxenkrug
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

Tryptophan (TRY) metabolism has recently emerged as an important link between dopaminergic hyperfunction/glutamatergic and cholinergic hypofunction and genetically regulated responses of the immune system in schizophrenia. In humans, TRY is an essential amino acid with two major metabolic pathways: the methoxyindole pathway, which leads to the formation of serotonin and, subsequently, melatonin; and the TRY–kynurenine pathway, which metabolizes about 95% of TRY and begins with the cleavage of the indole ring of TRY and the subsequent formation of kynurenine. This step is regulated in astrocytes by TRY-2,3-dioxygenase (TDO) and in microglia by indole-2,3-dioxygenase (IDO).

Article:

Kynurenine is further metabolized along two distinct routes:

  • the kynurenine–kynurenic acid (KYNA) pathway, regulated by kynurenine amino transferase (in both astrocytes and microglia) and resulting in production of KYNA, the only known endogenous N-methyl-D-aspartic acid (NMDA) antagonist; and
  • the kynurenine–(quinolinic acid)–nicotinic acid pathway, which is initiated by kynurenine hydroxylase in microglia, but not in astrocytes, and results in the production of NMDA agonists and free radical generators (e.g. quinolinic and picolinic acids), the precursors of nicotinic acid.

The crosstalk between the methoxyindole and kynurenine pathways is provided by NMDA-agonist-induced stimulation and NMDA-antagonistinduced inhibition of melatonin formation from serotonin, respectively. A type 1 immune response triggers microglial production of cytokines able to induce IDO. The most powerful inducer of IDO is interferon (IFN)-g. The other type-1 cytokine, tumor necrosis factor (TNF)-α, stimulates and/or drastically potentiates IFN-γ-induced IDO activity. Production of IFN-γ and TNF-α is controlled by (IFN-γ)+874 (T/A) and (TNF-α)-308 (G/A) genotypes, respectively. The high promoter T allele is associated with high IFN-γ production and increased IDO activity (i.e. elevated plasma kynurenine levels and kynurenine/tryptophan ratios) in healthy individuals. The presence of (TNF-α)-308 high promoter (A) may, therefore, strengthen the association between (IFN-γ)+874 high promoter (T) and IDO activity.

There are no published studies of IFN-γ gene polymorphism in schizophrenia. The TNF-α A allele is associated with high vulnerability to the late-onset paranoid-type schizophrenia in males. Genetic regulation of IDO may be affected by hormones; although IDO is not inducible by hormones, application of hydrocortisone, dexamethasone, and prolactin drastically potentiates IFN-γ-induced IDO, while the expression of the IFN-γ gene may be subject to direct hormonal control by estradiol and prolactin.

The type 2 immune response—which is predominant in schizophrenia—is characterized by inhibition of IDO in microglia and activation of TDO in astrocytes. Due to the the absence of kynurenine hydroxylase in astrocytes, activation of TDO results in a shift from the kynurenine–(quinolinic acid)–nicotinic acid to the kynurenine–KYNA pathway. Increased levels of KYNA in the brain (particularly in the prefrontal cortex) and cerebrospinal fluid (CSF) in schizophrenia may be accounted for by dopaminergic hyperfunction/glutaminergic hypofunction (and related clinical manifestations) in schizophrenia, as KYNA—the only known endogenous NMDA antagonist—activates mid-brain dopaminergic neurons similar to the effect of MK-801, an exogenous NMDA antagonist and psychotomimetic. Furthermore, the higher affinity of KYNA antagonism to a-7-nicotinic acetylcholine receptors than to NMDA receptors may explain the existence of cognitive impairment without psychotic symptoms, while psychotic symptoms are always associated with cognitive impairment.

Article Information:

Further Resources

Share this Article
Related Content In Psychiatric Disorders
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72