Kynurenine Pathway in Health and Disease

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 10934

Special Issue Editors

Department of Experimental and Clinical Pharmacology, Medical University of Lublin, 8b Jaczewskiego Str., 20-090 Lublin, Poland
Interests: epilepsy; neuropharmacology; zebrafish; behavioral neuroscience; genetic models; screening; deep phenotyping
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacology and Physiology, Drexel University College of Medicine; Philadelphia, PA 19102, USA
Interests: pharmacology; toxicology; central nervous system; epilepsy; schizophrenia; drug screening; plant-derived compounds

Special Issue Information

Dear Colleagues,

The kynurenine pathway is the primary route for tryptophan catabolism. Many substances of biological importance are formed on the kynurenine pathway (e.g., kynurenine, kynurenic acid, quinolinic acid). In the last decade, this pathway has received attention in the scientific community due to its involvement in inflammation, immune system function, and neurological disorders. Imbalance of this pathway leads to immune system activation and production of different compounds, also neurotoxic, making the kynurenine pathway a promising target for therapeutic intervention.

In this Special Issue of Cells on “Kynurenine Pathway in Health and Disease”, we invite colleagues from different fields (neurodevelopmental disorders, infectious and inflammatory disease, cancer, pharmacology, toxicology, etc.) conducting research on the kynurenine pathway to submit novel research articles. Review papers are also welcome.

Cells has an Impact Factor of 6.600 and is indexed in major scientific databases including Scopus, SCIE (Web of Science), PubMed, MEDLINE, and PMC.

Feel free to contact us should you have any questions.

We look forward to working with you in this Special Issue of Cells.

Dr. Kinga Gawel
Prof. Dr. Maciej Gasior
Guest Editors

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Published Papers (7 papers)

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Research

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16 pages, 332 KiB  
Article
Decreased Plasma Levels of Kynurenine and Kynurenic Acid in Previously Treated and First-Episode Antipsychotic-Naive Schizophrenia Patients
by Miloš Marković, Nataša Petronijević, Milena Stašević, Ivana Stašević Karličić, Milica Velimirović, Tihomir Stojković, Slavica Ristić, Mina Stojković, Nataša Milić and Tatjana Nikolić
Cells 2023, 12(24), 2814; https://doi.org/10.3390/cells12242814 - 11 Dec 2023
Viewed by 870
Abstract
Tryptophan (TRP) catabolites exert neuroactive effects, with the plethora of evidence suggesting that kynurenic acid (KYNA), a catabolite of the kynurenine pathway (KP), acts as the regulator of glutamate and acetylcholine in the brain, contributing to the schizophrenia pathophysiology. Newer evidence regarding measures [...] Read more.
Tryptophan (TRP) catabolites exert neuroactive effects, with the plethora of evidence suggesting that kynurenic acid (KYNA), a catabolite of the kynurenine pathway (KP), acts as the regulator of glutamate and acetylcholine in the brain, contributing to the schizophrenia pathophysiology. Newer evidence regarding measures of KP metabolites in the blood of schizophrenia patients and from the central nervous system suggest that blood levels of these metabolites by no means could reflect pathological changes of TRP degradation in the brain. The aim of this study was to investigate plasma concentrations of TRP, kynurenine (KYN) and KYNA at the acute phase and remission of schizophrenia in a prospective, case-control study of highly selected and matched schizophrenia patients and healthy individuals. Our study revealed significantly decreased KYN and KYNA in schizophrenia patients (p < 0.001), irrespective of illness state, type of antipsychotic treatment, number of episodes or illness duration and no differences in the KYN/TRP ratio between schizophrenia patients and healthy individuals. These findings could be interpreted as indices that kynurenine pathway might not be dysregulated in the periphery and that other factors contribute to observed disturbances in concentrations, but as our study had certain limitations, we cannot draw definite conclusions. Further studies, especially those exploring other body compartments that participate in kynurenine pathway, are needed. Full article
(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)
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23 pages, 2047 KiB  
Article
Developmental Exposure to Kynurenine Affects Zebrafish and Rat Behavior
by Marta Marszalek-Grabska, Kinga Gawel, Nataliia Kosheva, Tomasz Kocki and Waldemar A. Turski
Cells 2023, 12(18), 2224; https://doi.org/10.3390/cells12182224 - 06 Sep 2023
Cited by 1 | Viewed by 839
Abstract
Proper nutrition and supplementation during pregnancy and breastfeeding are crucial for the development of offspring. Kynurenine (KYN) is the central metabolite of the kynurenine pathway and a direct precursor of other metabolites that possess immunoprotective or neuroactive properties, with the ultimate effect on [...] Read more.
Proper nutrition and supplementation during pregnancy and breastfeeding are crucial for the development of offspring. Kynurenine (KYN) is the central metabolite of the kynurenine pathway and a direct precursor of other metabolites that possess immunoprotective or neuroactive properties, with the ultimate effect on fetal neurodevelopment. To date, no studies have evaluated the effects of KYN on early embryonic development. Thus, the aim of our study was to determine the effect of incubation of larvae with KYN in different developmental periods on the behavior of 5-day-old zebrafish. Additionally, the effects exerted by KYN administered on embryonic days 1–7 (ED 1–7) on the behavior of adult offspring of rats were elucidated. Our study revealed that the incubation with KYN induced changes in zebrafish behavior, especially when zebrafish embryos or larvae were incubated with KYN from 1 to 72 h post-fertilization (hpf) and from 49 to 72 hpf. KYN administered early during pregnancy induced subtle differences in the neurobehavioral development of adult offspring. Further research is required to understand the mechanism of these changes. The larval zebrafish model can be useful for studying disturbances in early brain development processes and their late behavioral consequences. The zebrafish-medium system may be applicable in monitoring drug metabolism in zebrafish. Full article
(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)
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11 pages, 3310 KiB  
Article
Differential Levels of Tryptophan–Kynurenine Pathway Metabolites in the Hippocampus, Anterior Temporal Lobe, and Neocortex in an Animal Model of Temporal Lobe Epilepsy
by Soumil Dey, Vivek Dubey, Aparna Banerjee Dixit, Manjari Tripathi, Poodipedi Sarat Chandra and Jyotirmoy Banerjee
Cells 2022, 11(22), 3560; https://doi.org/10.3390/cells11223560 - 10 Nov 2022
Cited by 1 | Viewed by 1212
Abstract
Glutamate-receptor-mediated hyperexcitability contributes to seizure generation in temporal lobe epilepsy (TLE). Tryptophan–kynurenine pathway (TKP) metabolites regulate glutamate receptor activity under physiological conditions. This study was designed to investigate alterations in the levels of TKP metabolites and the differential regulation of glutamatergic activity by [...] Read more.
Glutamate-receptor-mediated hyperexcitability contributes to seizure generation in temporal lobe epilepsy (TLE). Tryptophan–kynurenine pathway (TKP) metabolites regulate glutamate receptor activity under physiological conditions. This study was designed to investigate alterations in the levels of TKP metabolites and the differential regulation of glutamatergic activity by TKP metabolites in the hippocampus, anterior temporal lobe (ATL), and neocortex samples of a lithium–pilocarpine rat model of TLE. We observed that levels of tryptophan were reduced in the hippocampus and ATL samples but unaltered in the neocortex samples. The levels of kynurenic acid were reduced in the hippocampus samples and unaltered in the ATL and neocortex samples of the TLE rats. The levels of kynurenine were unaltered in all three regions of the TLE rats. The magnitude of reduction in these metabolites in all regions was unaltered in the TLE rats. The frequency and amplitude of spontaneous excitatory postsynaptic currents were enhanced in hippocampus ATL samples but not in the neocortex samples of the TLE rats. The exogenous application of kynurenic acid inhibited glutamatergic activity in the slice preparations of all these regions in both the control and the TLE rats. However, the magnitude of reduction in the frequency of kynurenic acid was higher in the hippocampus (18.44 ± 2.6% in control vs. 30.02 ± 1.5 in TLE rats) and ATL (16.31 ± 0.91% in control vs. 29.82 ± 3.08% in TLE rats) samples of the TLE rats. These findings suggest the differential regulation of glutamatergic activity by TKP metabolites in the hippocampus, ATL, and neocortex of TLE rats. Full article
(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)
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Review

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17 pages, 1163 KiB  
Review
A Review on the Role and Function of Cinnabarinic Acid, a “Forgotten” Metabolite of the Kynurenine Pathway
by Kinga Gawel
Cells 2024, 13(5), 453; https://doi.org/10.3390/cells13050453 - 05 Mar 2024
Viewed by 591
Abstract
In the human body, the majority of tryptophan is metabolized through the kynurenine pathway. This consists of several metabolites collectively called the kynurenines and includes, among others, kynurenic acid, L-kynurenine, or quinolinic acid. The wealth of metabolites, as well as the associated molecular targets [...] Read more.
In the human body, the majority of tryptophan is metabolized through the kynurenine pathway. This consists of several metabolites collectively called the kynurenines and includes, among others, kynurenic acid, L-kynurenine, or quinolinic acid. The wealth of metabolites, as well as the associated molecular targets and biological pathways, bring about a situation wherein even a slight imbalance in the kynurenine levels, both in the periphery and central nervous system, have broad consequences regarding general health. Cinnabarinic acid (CA) is the least known trace kynurenine, and its physiological and pathological roles are not widely understood. Some studies, however, indicate that it might be neuroprotective. Information on its hepatoprotective properties have also emerged, although these are pioneering studies and need to be replicated. Therefore, in this review, I aim to present and critically discuss the current knowledge on CA and its role in physiological and pathological settings to guide future studies. Full article
(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)
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18 pages, 1423 KiB  
Review
Glucocorticoid Hormones as Modulators of the Kynurenine Pathway in Chronic Pain Conditions
by Filip Jovanovic, Visnja Jovanovic and Nebojsa Nick Knezevic
Cells 2023, 12(8), 1178; https://doi.org/10.3390/cells12081178 - 18 Apr 2023
Cited by 3 | Viewed by 1906
Abstract
The pathogenesis of chronic pain entails a series of complex interactions among the nervous, immune, and endocrine systems. Defined as pain lasting or recurring for more than 3 months, chronic pain is becoming increasingly more prevalent among the US adult population. Pro-inflammatory cytokines [...] Read more.
The pathogenesis of chronic pain entails a series of complex interactions among the nervous, immune, and endocrine systems. Defined as pain lasting or recurring for more than 3 months, chronic pain is becoming increasingly more prevalent among the US adult population. Pro-inflammatory cytokines from persistent low-grade inflammation not only contribute to the development of chronic pain conditions, but also regulate various aspects of the tryptophan metabolism, especially that of the kynurenine pathway (KP). An elevated level of pro-inflammatory cytokines exerts similar regulatory effects on the hypothalamic–pituitary–adrenal (HPA) axis, an intricate system of neuro–endocrine–immune pathways and a major mechanism of the stress response. As the HPA axis counters inflammation through the secretion of endogenous cortisol, we review the role of cortisol along with that of exogenous glucocorticoids in patients with chronic pain conditions. Considering that different metabolites produced along the KP exhibit neuroprotective, neurotoxic, and pronociceptive properties, we also summarize evidence rendering them as reliable biomarkers in this patient population. While more in vivo studies are needed, we conclude that the interaction between glucocorticoid hormones and the KP poses an attractive venue of diagnostic and therapeutic potential in patients with chronic pain. Full article
(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)
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29 pages, 1063 KiB  
Review
Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder
by Yuki Murakami, Yukio Imamura, Yoshiyuki Kasahara, Chihiro Yoshida, Yuta Momono, Ke Fang, Daisuke Sakai, Yukuo Konishi and Toshimasa Nishiyama
Cells 2023, 12(7), 1087; https://doi.org/10.3390/cells12071087 - 04 Apr 2023
Cited by 3 | Viewed by 1971
Abstract
Several studies show that genetic and environmental factors contribute to the onset and progression of neurodevelopmental disorders. Maternal immune activation (MIA) during gestation is considered one of the major environmental factors driving this process. The kynurenine pathway (KP) is a major route of [...] Read more.
Several studies show that genetic and environmental factors contribute to the onset and progression of neurodevelopmental disorders. Maternal immune activation (MIA) during gestation is considered one of the major environmental factors driving this process. The kynurenine pathway (KP) is a major route of the essential amino acid L-tryptophan (Trp) catabolism in mammalian cells. Activation of the KP following neuro-inflammation can generate various endogenous neuroactive metabolites that may impact brain functions and behaviors. Additionally, neurotoxic metabolites and excitotoxicity cause long-term changes in the trophic support, glutamatergic system, and synaptic function following KP activation. Therefore, investigating the role of KP metabolites during neurodevelopment will likely promote further understanding of additional pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). In this review, we describe the changes in KP metabolism in the brain during pregnancy and represent how maternal inflammation and genetic factors influence the KP during development. We overview the patients with ASD clinical data and animal models designed to verify the role of perinatal KP elevation in long-lasting biochemical, neuropathological, and behavioral deficits later in life. Our review will help shed light on new therapeutic strategies and interventions targeting the KP for neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)
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26 pages, 1631 KiB  
Review
Kynurenine Pathway—An Underestimated Factor Modulating Innate Immunity in Sepsis-Induced Acute Kidney Injury?
by Anna Krupa, Mikolaj M. Krupa and Krystyna Pawlak
Cells 2022, 11(16), 2604; https://doi.org/10.3390/cells11162604 - 21 Aug 2022
Cited by 3 | Viewed by 2622
Abstract
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it accounts for about half of the cases of acute kidney injury (AKI). Although sepsis is the most frequent cause of AKI in critically ill patients, its pathophysiological [...] Read more.
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it accounts for about half of the cases of acute kidney injury (AKI). Although sepsis is the most frequent cause of AKI in critically ill patients, its pathophysiological mechanisms are not well understood. Sepsis has the ability to modulate the function of cells belonging to the innate immune system. Increased activity of indoleamine 2,3-dioxygenase 1 (IDO1) and production of kynurenines are the major metabolic pathways utilized by innate immunity cells to maintain immunological tolerance. The activation of the kynurenine pathway (KP) plays a dual role in sepsis—in the early stage, the induction of IDO1 elicits strong proinflammatory effects that may lead to tissue damage and septic shock. Afterwards, depletion of tryptophan and production of kynurenines contribute to the development of immunosuppression that may cause the inability to overpower opportunistic infections. The presented review provides available data on the various interdependencies between elements of innate immunity and sepsis-induced AKI (SAKI) with particular emphasis on the immunomodulatory significance of KP in the above processes. We believe that KP activation may be one of the crucial, though underestimated, components of a deregulated host response to infection during SAKI. Full article
(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)
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