| 1 | Neurobiol. Dis. 2004 Apr 15: 618-29 |
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| PMID | 15056470 |
| Title | Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. |
| Abstract | Markers of the kynurenine pathway were studied in postmortem frontal cortex obtained from individuals with schizophrenia and controls. Quantitative endpoint RT-PCR was used to measure mRNA transcripts. Of the two enzymes capable of catalyzing the first step in the pathway, tryptophan 2,3-dioxygenase (TDO2) and indoleamine dioxygenase (IDO), the concentration of mRNA for TDO2 was found to be elevated 1.6-fold in the schizophrenia group (P = 0.03), whereas the concentration of the mRNA for IDO was not significantly different between the schizophrenia and control groups. Immunohistochemistry showed an increased density of TDO2-immunopositive astroglial cells in the white matter of patients with schizophrenia (P = 0.04). Neurons and vessels were also immunopositive for TDO2, but there were no significant differences in labeling of these structures between the two groups. These results add to the evidence that kynurenine pathway changes might be involved in the pathogenesis of schizophrenia and the schizophrenia-like psychoses of other disorders. |
| SCZ Keywords | schizophrenia |
| 2 | Brain Res. 2006 Feb 1073-1074: 25-37 |
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| PMID | 16448631 |
| Title | Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. |
| Abstract | Upregulation of the kynurenine pathway has been associated with several etiologies of psychosis, an indication that increased levels of pathway intermediates might be involved in eliciting some psychotic features. In schizophrenia, tryptophan 2,3-dioxygenase (TDO2) was previously identified in postmortem frontal cortex as the enzyme likely responsible for the reported increase in pathway activity in the brain. For this follow-up study of postmortem anterior cingulate gyrus, we have found evidence of increased TDO2 activity in schizophrenia at three different levels of regulation: mRNA, protein, and metabolic product. The results were unaffected by neuroleptic status or smoking history. To make the distinction between mental disorders with psychosis and those without, this study included patients with bipolar disorder and major depression. Compared to the control group, the HPLC, RT-PCR, and immunohistochemistry results show significant elevation of (1) kynurenine in schizophrenia (1.9-fold, P = 0.02), and in bipolar disorder (1.8-fold, P = 0.04), primarily in the bipolar subgroup with psychosis (2.1-fold, P = 0.03); (2) TDO2 mRNA in schizophrenia (1.7-fold; P = 0.049); and (3) the immunohistochemistry values for the density of TDO2-positive white matter glial cells in schizophrenia (P = 0.01) and in major depression (P = 0.03) as well as the density and intensity of glial cells (in both gray and white matter) stained for TDO2 in bipolar disorder (P = 0.02). Unlike the results for schizophrenia and bipolar disorder, the increase in TDO2 protein in the major depression group was not associated with an increase in kynurenine concentration. |
| SCZ Keywords | schizophrenia |
| 3 | Neurochem. Int. 2008 May 52: 1297-303 |
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| PMID | 18328600 |
| Title | Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder. |
| Abstract | Increased concentrations of kynurenine pathway metabolites have been reported by several groups for disorders involving psychosis, including schizophrenia and bipolar disorder. To identify components of the pathway that may be relevant as biomarkers or may underlie the etiology of psychosis, it is essential to characterize the extent of kynurenine pathway activation and to investigate known regulators of one of the key kynurenine-producing enzymes, tryptophan 2,3-dioxygenase (TDO2), previously shown in this laboratory to be increased commensurate with kynurenine in postmortem anterior cingulate brain tissue from individuals with schizophrenia. Using this same anterior cingulate sample set from individuals with schizophrenia, bipolar disorder, depression and controls (N=12-14 per group), we measured the precursor of kynurenine and two downstream products. The precursor, tryptophan, was significantly increased only in the schizophrenia group (1.54-fold the mean control value, p=0.02), and through substrate-induced activation, may be one cause of the increased kynurenine and kynurenine metabolites. This finding for tryptophan differs from some, but not all, previous reports and methodological reasons for the discrepancies are discussed. A product of kynurenine metabolism, 3-OH-anthranilic acid was also significantly increased only in the schizophrenia group (1.68-fold the mean control value, p=0.03). 3-OH-anthranilic acid is a reactive species with cytotoxic properties, although the threshold for such effects is not known for neurons. Analysis of major pre- and post-mortem variables showed that none were confounding for these between-group experimental comparisons. Nicotinamide, a pathway end product, did not differ between groups but was associated with cause of death (suicide) within the bipolar group (p=0.03). |
| SCZ Keywords | schizophrenia |
| 4 | Schizophr. Res. 2009 Sep 113: 259-67 |
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| PMID | 19502010 |
| Title | Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder. |
| Abstract | Prior studies of mRNA expression, protein expression, and pathway metabolite levels have implicated dysregulation of the kynurenine pathway in the etiology of schizophrenia and bipolar disorder. Here we investigate whether genes involved in kynurenine pathway regulation might interact with genes that respond to kynurenine metabolites, to enhance risk for these psychiatric phenotypes. Candidate genes were selected from prior studies of genetic association, gene expression profiling and animal models. A single nucleotide polymorphism (SNP) in each of six genes, TDO2, HM74, HM74A, MCHR1, MCHR2 and MC5R, was tested for association with phenotype (475 Caucasians, 88 African Americans with schizophrenia; 97 Caucasians, 3 African Americans with bipolar disorder; 191 Caucasian, 49 African American controls). An A allele in HM74 was significantly associated with schizophrenia and with schizophrenia plus bipolar disorder combined, odds ratios (OR) of 1.48, p=0.011 and 1.50, p=0.007, respectively. Augmentation of disease risk was found for the complex genotype HM74[A,any]+MCHR1[T,any]+MCHR2[C,any] which conferred an OR maximal for the combined diagnostic category of schizophrenia plus bipolar disorder (1.70, p=0.003), carried by 30% of the cases. TDO2[CC]+MC5R[G, any]+MCHR2[GC] conferred an OR maximal for schizophrenia alone (4.84, p=0.005), carried by 8% of schizophrenia cases. The combined risk posed by these related, complex genotypes is greater than any identified single locus and may derive from co-regulation of the kynurenine pathway by interacting genes, a lack of adequate melanotropin-controlled sequestration of the kynurenine-derived pigments, or the production of melanotropin receptor ligands through kynurenine metabolism. |
| SCZ Keywords | schizophrenia |
| 5 | Neuropharmacology 2016 May -1: -1 |
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| PMID | 27245499 |
| Title | The kynurenine pathway in schizophrenia and bipolar disorder. |
| Abstract | The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-D-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments. Contributing to enhanced production of kynurenic acid, the expression and enzyme activity of kynurenine 3-monooxygenase (KMO) are reduced in schizophrenia and in bipolar patients with a history of psychosis. The kynurenine pathway is also critically regulated by cytokines, and, indeed, the pro-inflammatory cytokines interleukin (IL)-1? and IL-6 are elevated in schizophrenia and bipolar disorder and stimulate the production of kynurenic acid. One physiological mechanism controlling the activity of the kynurenine pathway originates from the protein sorting nexin 7 (SNX7). This glial signaling pathway initiates a caspase-8-driven activation of IL-1? that induces tryptophan-2,3-dioxygenase 2 (TDO2), an enzyme in the kynurenine pathway. A recent study shows that a genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of kynurenic acid and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Experimental studies highlight the detrimental effects of increased synthesis of kynurenic acid during sensitive periods of early brain development. Furthermore, experimental studies strongly support inhibition of kynurenine aminotransferase (KAT) II as a novel target and a valuable pharmacological strategy in the treatment of psychosis and for improving cognitive performance relevant for schizophrenia. |
| SCZ Keywords | schizophrenia |