Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder

Miller, Christine L.; Llenos, Ida C.; Dulay, Jeannette R.; Weis, Serge

doi:10.1016/j.brainres.2005.12.056

Cited by 214 publications

(183 citation statements)

References 67 publications

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“…Indeed, increased TDO activity in the postmortem brains of patients with schizophrenia has been reported. 22,43 In line with this, the present study shows that fetal human cortical astrocytes respond to application of IL 6 with an in creased KYNA synthesis, suggesting an intimate interplay between IL 6 and the KYN pathway.…”

Section: Discussionsupporting

confidence: 87%

“…18 Indeed, in patients with schizophrenia and those with bipolar disorder with psychosis, elevated levels of KYNA and its precursor KYN in the CSF or in the postmortem brain have been consistently reported. [19][20][21][22][23][24][25][26] The aim of the present study, using a well characterized cohort of olanzapine treated patients with chronic schizo phrenia, was to investigate CSF levels of cytokines and cor relate those to previously measured levels of tryptophan metab olites of the KYN pathway in the same patients. Fur ther, since an association between CSF IL 6 and the produc tion of KYNA has been found in patients, as reflected by the tryptophan:KYNA ratio, we investigated a putative interplay between this cytokine and the production of KYNA in hu man astrocyte cultures.…”

Section: Introductionmentioning

confidence: 99%

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Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Schwieler

Larsson

Skogh

et al. 2015

jpn

181

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IntroductionThe role of immune activation in schizophrenia has received increasing interest in recent years. Epidemiological studies have shown that infections and autoimmune diseases are clin ic ally important risk factors for the development of schizo phrenia. [1][2][3] Furthermore, a recent study integrating results from a meta analysis of genome wide association studies in schizophrenia found that the most significant changes were observed in genetic loci related to the immune system. 4 Also, patients with schizophrenia show microglial activation, as re vealed by positron emission tomography. 5,6 Further, postmor tem studies using messenger RNA (mRNA) expression or im munohistochemical detection have shown increased levels of immune related compounds. 7-9 A number of investigations have focused on cytokines, but these studies have not yielded a unanimous picture, possibly because of a number of con founding factors, such as smoking and dietary habits, body mass index (BMI), type and duration of antipsychotic treat ment and drug abuse -all factors potentially affecting the Background: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. Methods: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were ana lyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. Results: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. Limitations: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. Conclusion: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-d-aspartate receptor antagonist KYNA in patients with schizophrenia.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Schwieler

Larsson

Skogh

et al. 2015

jpn

181

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“…Additional support to this hypothesis is that IDO and kynurenine pathway metabolites regulate the activation of myelin-specific T cells (Platten et al, 2005) that can directly contribute to demyelination and indirectly potentiate antibodies against myelin proteins (Kroenke and Segal, 2011;Vass et al, 1992). However, in the brain TDO mRNA and protein, but not IDO, is upregulated in schizophrenia (Miller et al, 2004;Miller et al, 2006). Furthermore, given that fasting tryptophan levels, but not KYN/TRP ratios, were correlated with whole-brain tract-averaged FA in patients, it is also worth considering that this relationship is related to reduced availability of tryptophan.…”

Section: Discussionmentioning

confidence: 97%

“…Evidence of altered activity of the kynurenine pathway in schizophrenia includes findings of increased concentration of kynurenine and kynurenic acid in brain tissue (Schwarcz et al, 2001;Miller et al, 2006;Sathyasaikumar et al, 2011) and in cerebrospinal fluid of schizophrenia patients (Nilsson et al, 2005;Linderholm et al, 2012). Kynurenine and kynurenic acid administration to the prefrontal cortex significantly decrease extracellular glutamate levels in rodents Konradsson-Geuken et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Chiappelli

Postolache

Kochunov

et al. 2016

Neuropsychopharmacol

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Schizophrenia is associated with abnormalities in the structure and functioning of white matter, but the underlying neuropathology is unclear. We hypothesized that increased tryptophan degradation in the kynurenine pathway could be associated with white matter microstructure and biochemistry, potentially contributing to white matter abnormalities in schizophrenia. To test this, fasting plasma samples were obtained from 37 schizophrenia patients and 38 healthy controls and levels of total tryptophan and its metabolite kynurenine were assessed. The ratio of kynurenine to tryptophan was used as an index of tryptophan catabolic activity in this pathway. White matter structure and function were assessed by diffusion tensor imaging (DTI) and 1 H magnetic resonance spectroscopy (MRS). Tryptophan levels were significantly lower (po0.001), and kynurenine/tryptophan ratios were correspondingly higher (p = 0.018) in patients compared with controls. In patients, lower plasma tryptophan levels corresponded to lower structural integrity (DTI fractional anisotropy) (r = 0.347, p = 0.038). In both patients and controls, the kynurenine/tryptophan ratio was inversely correlated with frontal white matter glutamate level (r = − 0.391 and − 0.350 respectively, p = 0.024 and 0.036). These results provide initial evidence implicating abnormal tryptophan/ kynurenine pathway activity in changes to white matter integrity and white matter glutamate in schizophrenia.

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“…In addition, IDO has been implicated in a diverse range of physiological and pathological conditions, including suppression of T cell proliferation, maternal tolerance to allogenic fetus, and immune escape of cancers (4)(5)(6)(7)(8), and is an attractive target for drug discovery against cancer and autoimmune and other diseases (2,(9)(10)(11)(12).…”

mentioning

confidence: 99%

Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase

Forouhar

Anderson

Mowat

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

169

284

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Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) constitute an important, yet relatively poorly understood, family of heme-containing enzymes. Here, we report extensive structural and biochemical studies of the Xanthomonas campestris TDO and a related protein SO4414 from Shewanella oneidensis, including the structure at 1.6-Å resolution of the catalytically active, ferrous form of TDO in a binary complex with the substrate L-Trp. The carboxylate and ammonium moieties of tryptophan are recognized by electrostatic and hydrogen-bonding interactions with the enzyme and a propionate group of the heme, thus defining the L-stereospecificity. A second, possibly allosteric, L-Trp-binding site is present at the tetramer interface. The sixth coordination site of the heme-iron is vacant, providing a dioxygenbinding site that would also involve interactions with the ammonium moiety of L-Trp and the amide nitrogen of a glycine residue. The indole ring is positioned correctly for oxygenation at the C2 and C3 atoms. The active site is fully formed only in the binary complex, and biochemical experiments confirm this induced-fit behavior of the enzyme. The active site is completely devoid of water during catalysis, which is supported by our electrochemical studies showing significant stabilization of the enzyme upon substrate binding.cancer ͉ heme enzymes ͉ immunomodulation ͉ indoleamine 2,3-dioxygenase T ryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) catalyze the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring, the first and rate-limiting step in L-Trp catabolism through the kynurenine pathway (1-3). In addition, IDO has been implicated in a diverse range of physiological and pathological conditions, including suppression of T cell proliferation, maternal tolerance to allogenic fetus, and immune escape of cancers (4-8), and is an attractive target for drug discovery against cancer and autoimmune and other diseases (2, 9-12).Despite catalyzing identical biochemical reactions (Fig. 1a), the sequence similarity between TDO and IDO is extremely low. An alignment of their sequences is only possible based on their structures, which suggests a sequence identity of 10% between them (Fig. 1b). In comparison, Xanthomonas campestris TDO shares 34% sequence identity with human TDO (Fig. 1b), demonstrating the remarkable evolutionary conservation of this enzyme. TDO is a homotetrameric enzyme and is highly specific for L-Trp and related derivatives such as 6-fluoro-Trp as the substrate. In comparison, IDO is monomeric, and shows activity toward a larger collection of substrates, including L-Trp, Dtryptophan (D-Trp), serotonin, and tryptamine (3), although the K m for D-Trp is Ϸ100-fold higher than that for L-Trp (13). The structure of human IDO in the catalytically inactive, ferric [Fe(III)]-heme state in complex with the 4-phenylimidazole inhibitor has recently been reported (14). Although this structure gave information about important active site residues, the inhibitor is coordinat...

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Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder

Cited by 214 publications

References 67 publications

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase

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