Quinolinic acid (QUIN), a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF) and is often implicated in ...the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA) receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death.
Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor α has been observed during acute episodes of major depression. These ...peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described.
Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects.
Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD.
These results add a novel link to the immune hypothesis of depression by providing evidence for an upregulation of microglial QUIN in brain regions known to be responsive to infusion of NMDA antagonists such as ketamine. Further work in this area could lead to a greater understanding of the pathophysiology of depressive disorders and pave the way for novel NMDA receptor therapies or immune-modulating strategies.
Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing ...in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.
Min Yang,1– 3,* Wenfei Wang,3,* Peize Zhang,4 Guizhen Liu,5 Hailin Lu,6 Mingjie He,5 Guofang Deng,2,3 Xiaoyou Chen1,7 1Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research ...Institute, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Second Department of Pulmonary Medicine and Tuberculosis, the Third People’s Hospital of Shenzhen, Southern University of Science and Technology, Shenzhen, Guangdong, People’s Republic of China; 3National Clinical Research Center for Infectious Disease, the Third People’s Hospital of Shenzhen, Southern University of Science and Technology, Shenzhen, Guangdong, People’s Republic of China; 4Fourth Department of Pulmonary Medicine and Tuberculosis, the Third People’s Hospital of Shenzhen, Southern University of Science and Technology, Shenzhen, Guangdong, People’s Republic of China; 5The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, People’s Republic of China; 6Gannan Medical University, Ganzhou, Jiangxi, People’s Republic of China; 7Infectious Diseases Department, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyou Chen; Guofang Deng, Email chenxy1998@hotmail.com; jxxk1035@yeah.netObjective: We aimed to investigate dysregulated metabolic pathways and identify diagnostic and therapeutic targets in patients with tuberculosis-diabetes (TB-DM).Methods: In our prospective cohort study, plasma samples were collected from healthy individuals, diabetic (DM) patients, untreated TB-only (TB-0)/TB-DM patients (TB-DM-0), and cured TB (TB-6)/TB-DM patients (TB-DM-6) to measure the levels of amino acids, fatty acids, and other metabolites in plasma using high-throughput targeted quantification methods.Results: Significantly different biological processes and biomarkers were identified in DM, TB-DM-0, and TB-DM-6 patients. Moreover, quinolinic acid (QA) showed excellent predictive accuracy for distinguishing between DM patients and TB-DM-0 patients, with an AUC of 1 (95% CI 1– 1). When differentiating between TB-DM-0 patients and TB-DM-6 patients, the AUC was 0.9297 (95% CI 0.8460– 1). Compared to those in DM patients, the QA levels were significantly elevated in TB-DM-0 patients and decreased significantly after antituberculosis treatment. We simultaneously compared healthy controls and untreated tuberculosis patients and detected an increase in the level of QA in the plasma of tuberculosis patients, which decreased following treatment.Conclusion: These findings improve the current understanding of tuberculosis treatment in patients with diabetes. QA may serve as an ideal diagnostic biomarker for TB-DM patients and contribute to the development of more effective treatments.Keywords: pulmonary tuberculosis, diabetes, metabolomics, quinolinic acid, biomarker
•Effect of non-Saccharomyces yeasts on amino acid derivatives was studied in wine.•Picolinic acid and quinolinic acid were found in wine for the first time.•Tryptophan ethyl ester content increased ...during alcoholic fermentation of wines.•O. oeni malolactic fermentation affected the content of kynurenic acid in red wine.•Different concentrations of amino acid derivatives were detected in laboratory and large-scale processing of wines.
This study aimed to investigate the effect of commercial non-Saccharomyces yeasts and Oenococcus oeni on the formation of amino acid derivatives, some of which have neuroactive properties, during fermentation in laboratory-scale processing of white and red wines. Changes in the content of amino acid derivatives during fermentation of large-scale white and red wines were also evaluated. The highest kynurenic, picolinic, and quinolinic acid concentrations were observed in white wine fermented with Torulaspora delbrueckii, Kluyveromyces thermotolerans and Saccharomyces cerevisiae simultaneously. No changes in the content of picolinic and kynurenic acid were observed during large-scale white wine fermentation. Tryptophan ethyl ester concentration in all wines increased significantly during alcoholic fermentation. Natural and O. oeni malolactic fermentation did not alter the content of picolinic acid, a neuroprotective compound, in red wine. The decrease in the content of tyramine, phenylethylamine, and dopamine in laboratory-scale white wines was observed during alcoholic fermentation.
One intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington's disease. Our aim is to evaluate the effects of the cysteinyl ...leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions.
The right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using
F-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a
F-FDG PET study at baseline and 4 months after lesion.
F-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method.
MLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK-compared to VEH-treated rats.
F-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres.
Overall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.
Cancer is the second leading cause of mortality worldwide. The development of anticancer therapy plays a crucial role in mitigating tumour progression and metastasis. Epithelioid hemangioendothelioma ...is a very rare cancer, however, with a high systemic involvement. Kynurenine metabolites which include l‐kynurenine, 3‐hydroxykynurenine, 3‐hydroxyanthranilic acid and quinolinic acid have been shown to inhibit T‐cell proliferation resulting in a decrease in cell growth of natural killer cells and T cells. Furthermore, metabolites such as
l‐kynurenine have been shown to inhibit proliferation of melanoma cells in vitro. Considering these metabolite properties, the present study aimed to explore the in vitro effects of
l‐kynurenine, quinolinic acid and kynurenic acid on endothelioma sEnd‐2 cells and on endothelial (EA. hy926 cells) (control cell line). The in vitro effect at 24, 48, and 72 h exposure to a range of 1−4 mM of the respective kynurenine metabolites on the two cell lines in terms of cell morphology, cell cycle progression and induction of apoptosis was assessed. The half inhibitory concentration (IC50), as determined using nonlinear regression, for
l‐kynurenine, quinolinic acid and kynurenic acid was 9.17, 15.56, and 535.40 mM, respectively. Optical transmitted light differential interference contrast and hematoxylin and eosin staining revealed cells blocked in metaphase, formation of apoptotic bodies and compromised cell density in
l‐kynurenine‐treated cells. A statistically significant increase in the number of cells present in the sub‐G1 phase was observed in
l‐kynurenine‐treated sample. To our knowledge, this was the first in vitro study conducted to investigate the mechanism of action of kynurenine metabolites on endothelioma sEnd‐2 cells. It can be concluded that
l‐kynurenine exerts an antiproliferative effect on the endothelioma sEnd‐2 cell line by decreasing cell growth and proliferation as well as a metaphase block. These hallmarks suggest cell death via apoptosis. Further research will be conducted on
l‐kynurenine to assess the effect on cell adhesion in vitro and in vivo as cell‐cell adhesion has been shown to increase metastasis to distant organs therefore, the inhibition of adhesion may lead to a decrease in metastasis.
Significance statement
Kynurenine metabolites have been shown to inhibit cell proliferation in melanoma cells, however the effect of kynurenine metabolites on cell morphology and proliferation has not been previously investigated in endothelioma cells. Cell morphology was investigated using light microscopy, it revealed the formation of apoptotic bodies and metaphase block in l‐kynurenine‐treated sample. A statistically significant increase in the sub‐G1 phase of cell cycle was observed in endothelioma cells treated with
l‐kynurenine.
l‐kynurenine was identified as a promising antiproliferative kynurenine metabolite. The antiproliferative effect of
l‐kynurenine has not been previously reported in endothelioma.
Highlights • We measured serum concentrations of kynurenine metabolites in bipolar disorder (BD). • We also measured gray matter volume of the hippocampus and amygdala in BD. • The ratio of kynurenic ...acid (KynA) to quinolinic acid (QA) was reduced in BD. • The ratio of KynA/3-hydroxykynurenine was correlated with hippocampal volume in BD. • Abnormalities in kynurenine metabolism may impact the structure of the hippocampus.
Highlights • The ratio of kynurenic acid (KynA) to quinolinic acid (QA) was reduced in MDD. • KynA/QA was not associated with striatal volume in the MDD group. • Activation of the kynurenine pathway ...was associated with striatal volume in MDD.
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