1J Psychiatr Res 2013 Nov 47: 1815-23
TitleActivation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine.
AbstractAccumulating data suggest a causative link between immune stimulation, disturbed metabolism of tryptophan, and pathogenesis of bipolar disorder and schizophrenia. The goal of this study was to examine the production of KYNUrenic acid (KYNA), 3-hydroxyKYNUrenine (3-HK) and the expression of KYNUrenine pathway enzymes involved in their synthesis and metabolism in cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals. The assessment was performed under basal conditions or following treatment with interferon (IFN)-?, tumor necrosis factor (TNF)-?, interleukin (IL)-1?, IL-6, or their combinations, in cells exposed to exogenous KYNUrenine. In both groups of patients, the baseline production of KYNA and 3-HK was increased, as compared to control subjects. Case-treatment analyses revealed significant interactions between bipolar case status and IL-1?, IL-6, IFN-? + TNF-?, or IFN-? + IL-1?, as well as between schizophrenia case status and IL-1?, IFN-? + TNF-?, or IFN-? + IL-1?, in terms of higher 3-HK. Noteworthy, no case-treatment interactions in terms of KYNA production were found. Observed changes did not appear to correlate with the expression of genes encoding KYNUrenine aminotransferases (KATs), KYNUreninase (KYNU) or KYNUrenine-3-monooxygenase (KMO). The single nucleotide polymorphisms (SNPs), rs1053230 and rs2275163, in KMO influenced KYNA levels yet did not explain the case-treatment discrepancies. In conclusion, our present findings indicate the utility of skin-derived fibroblasts for KYNUrenines research and support the concept of KYNUrenine pathway alterations in bipolar disorder and schizophrenia. The increase in ratio between neurotoxic 3-HK and neuroinhibitory/neuroprotective KYNA following exposure to cytokines may account for altered neurogenesis and structural abnormalities characteristic for both diseases.
SCZ Keywordsschizophrenia
2J. Physiol. Pharmacol. 2016 Feb 67: 3-19
TitleOverview of the role of vitamins and minerals on the kynurenine pathway in health and disease.
AbstractThe KYNUrenine pathway (KP) of L-tryptophan metabolism produces several neuroactive metabolites with an amino acid structure. These metabolites may play an important role in the pathophysiology of irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, AIDS-dementia complex, depression, epilepsy and the aging process. Modulation of the KP through inhibition or stimulation of enzyme synthesis and activity can be an alternative approach to traditional therapy. Furthermore, it may be responsible for the altered functioning of the enteric nervous system and the central nervous system. There is evidence that the KP is sensitive to changes in the concentration of many vitamins and minerals that play a crucial role as coenzymes and cofactors in the de novo synthesis of nicotinamide adenine dinucleotide coenzyme. A reduction in the availability of the active form of vitamin B6 (pyridoxal 5'-phosphate, PLP) is known to affect tryptophan hydroxylase, KYNUrenine aminotransferase and KYNUreninase (KYNU). Vitamin B2 deficiencies result in a reduction in the activity of the flavin adenine dinucleotide dependent enzyme, KYNUrenine 3-monooxygenase. Minerals are also responsible for the proper functioning of enzymes engaged in L-tryptophan metabolism. Mn(2+), Zn(2+), Co(2+) and Cu(2+) influence KYNU activity, and Mg(2+) regulates quinolinate phosphoribosyl transferase. Fe(2+) is responsible for the proper functioning of both indoleamine 2,3-dioxygenase and 3-hydroxy-anthranilic acid dioxygenase. Changes in the concentration of KP metabolites and in enzymatic activity have been found in many pathological states. Therefore, it is justifiable to regulate the concentration of certain KYNUrenines or enzymes in the KP which may provide a potential therapeutic target for the treatment of various health impairments. This review demonstrates the role of vitamin and mineral activity on the KP, which may have an effect on the proper functioning of the human organism. Surplus administration of vitamins did not elicit any beneficial effects on L-tryptophan metabolism. Whether a mineral surplus influences L-tryptophan metabolism is still not established. It seems that cofactor deficiencies influence the KP far more than surpluses.
SCZ Keywordsschizophrenia