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Kynurenic Acid: Emerging Research Advances and Therapeutic Implications
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Kynurenic Acid: Emerging Research Advances and Therapeutic Implications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 20 November 2024 | Viewed by 7318

Special Issue Editors

Prof. Dr. Piotr Paluszkiewicz

E-Mail Website
Guest Editor
Department of General, Oncological and Metabolic Surgery, Institute of Haematology and Transfusion Medicine, 02-778 Warsaw, Poland
Interests: kynurenines; cancer biology; pancreas; colon; clinical chemistry; surgery and surgical oncology; clinical pharmacology; blood coagulation disorders
Dr. Monika Turska-Kozłowska

E-Mail Website
Guest Editor
Institute of Biological Sciences, The John Paul II Catholic University of Lublin, Konstantynów 1 H, 20-708 Lublin, Poland
Interests: kynurenic acid; kynurenine pathway; diet; food

Special Issue Information

Dear Colleagues,

The kynurenine pathway is the main route for tryptophan degradation, and kynurenine is a central downstream metabolite. Kynurenic acid is the end product of kynurenine enzymatic transamination, and the role of kynurenic acid has been widely explored. Imbalances in the kynurenine pathway have been observed in many states, ranging from inflammation to cancer formation and immunological responses. Moreover, the role of kynurenines in organism growth and development in mammals, the regulation of energy expenditure, and signaling in the gut–brain axis has been considered.

Environmental exposure to kynurenic acid is under debate; however, endoluminal synthesis has been connected to some microbiota. Additionally, the presence of kynurenic acid in food has been confirmed. The fast absorption in the upper gut in mammals should open the door for further studies on the impact of exposure to kynurenic acid on inflammatory responses, carcinogenesis, and immunomodulatory action. To date, the mechanisms of action of kynurenic acid have only been partially understood, including receptor activation or non-receptor modulation of the kynurenine pathway. The observed effects suggest the potential use of kynurenic acid or its analogues as pharmacologically active compounds for inflammatory, metabolic, or immunomodulatory activities. These effects can be potentially harnessed through specific modifications of diets and used for prevention or supportive therapy.

Prof. Dr. Piotr Paluszkiewicz
Dr. Monika Turska-Kozłowska
Guest Editors

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Keywords

  • kynurenic acid
  • kynurenine pathway
  • kynurenine
  • therapeutic use
  • supply and distribution

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Published Papers (6 papers)

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Research

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24 pages, 14594 KiB  
Article
KYNA Ameliorates Glutamate Toxicity of HAND by Enhancing Glutamate Uptake in A2 Astrocytes
by Jie Chen, Jinhu Zou, Pengwei Huang, Xuefeng Gao, Jingxian Lun, Yubin Li, Zelong Gong and Hong Cao
Int. J. Mol. Sci. 2024, 25(8), 4286; https://doi.org/10.3390/ijms25084286 - 12 Apr 2024
Cited by 1 | Viewed by 1148
Abstract
Reactive astrocytes are key players in HIV-associated neurocognitive disorders (HAND), and different types of reactive astrocytes play opposing roles in the neuropathologic progression of HAND. A recent study by our group found that gp120 mediates A1 astrocytes (neurotoxicity), which secrete proinflammatory factors and [...] Read more.
Reactive astrocytes are key players in HIV-associated neurocognitive disorders (HAND), and different types of reactive astrocytes play opposing roles in the neuropathologic progression of HAND. A recent study by our group found that gp120 mediates A1 astrocytes (neurotoxicity), which secrete proinflammatory factors and promote HAND disease progression. Here, by comparing the expression of A2 astrocyte (neuroprotective) markers in the brains of gp120 tgm mice and gp120+/α7nAChR−/− mice, we found that inhibition of alpha 7 nicotinic acetylcholine receptor (α7nAChR) promotes A2 astrocyte generation. Notably, kynurenine acid (KYNA) is an antagonist of α7nAChR, and is able to promote the formation of A2 astrocytes, the secretion of neurotrophic factors, and the enhancement of glutamate uptake through blocking the activation of α7nAChR/NF-κB signaling. In addition, learning, memory and mood disorders were significantly improved in gp120 tgm mice by intraperitoneal injection of kynurenine (KYN) and probenecid (PROB). Meanwhile, the number of A2 astrocytes in the mouse brain was significantly increased and glutamate toxicity was reduced. Taken together, KYNA was able to promote A2 astrocyte production and neurotrophic factor secretion, reduce glutamate toxicity, and ameliorate gp120-induced neuropathological deficits. These findings contribute to our understanding of the role that reactive astrocytes play in the development of HAND pathology and provide new evidence for the treatment of HAND via the tryptophan pathway. Full article
(This article belongs to the Special Issue Kynurenic Acid: Emerging Research Advances and Therapeutic Implications)
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15 pages, 1496 KiB  
Article
Different Kynurenine Pathway Dysregulation in Systemic Sclerosis in Men and Women
by Monika Turska-Kozłowska, Bruno Pedraz-Petrozzi, Piotr Paluszkiewicz and Jolanta Parada-Turska
Int. J. Mol. Sci. 2024, 25(7), 3842; https://doi.org/10.3390/ijms25073842 - 29 Mar 2024
Cited by 1 | Viewed by 965
Abstract
Systemic sclerosis (SSc), a predominantly female-affected systemic autoimmune disease, requires tailored treatment strategies contingent on organ involvement and symptom severity. Given SSc’s inflammatory nature, the involvement of the kynurenine pathway (KP) in its pathophysiology is underexplored. Our study aimed to investigate sex-related differences [...] Read more.
Systemic sclerosis (SSc), a predominantly female-affected systemic autoimmune disease, requires tailored treatment strategies contingent on organ involvement and symptom severity. Given SSc’s inflammatory nature, the involvement of the kynurenine pathway (KP) in its pathophysiology is underexplored. Our study aimed to investigate sex-related differences in KP activation among SSc patients and assess the impact of angiotensin-converting enzyme (ACE) inhibitors and estimated glomerular filtration rate (eGFR) on KP metabolite concentrations. We enrolled 48 SSc patients and 53 healthy controls, quantifying KP metabolites (tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA)) in serum via high-performance liquid chromatography. Separate multivariate analyses of covariance (MANCOVAs) for women and men were performed to ascertain mean differences between patients and healthy controls while correcting for age. For our secondary objective, we conducted a MANCOVA to explore disparities in ACE inhibitor users and non-users among patients, with BMI correction. Our findings revealed decreased TRP concentrations but increased KYNA/TRP ratio and KYN/TRP ratio in both male and female SSc patients compared to their respective controls. Unlike women, SSc males exhibited higher KYN concentrations and decreased KYNA/KYN ratio relative to their controls. Additionally, SSc patients using ACE inhibitors had higher serum KYNA levels than non-users. Notably, we established a significant correlation between eGFR and KYNA in SSc patients. These results indicate differential KP activation in male and female SSc patients, with males demonstrating heightened KP activation. While ACE inhibitors may influence the KP in SSc patients, further research is necessary to comprehensively understand their impact on symptoms and prognosis in the context of these KP alterations. Full article
(This article belongs to the Special Issue Kynurenic Acid: Emerging Research Advances and Therapeutic Implications)
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Review

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42 pages, 1823 KiB  
Review
The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy
by Trevor W. Stone, L. Gail Darlington, Abdulla A.-B. Badawy and Richard O. Williams
Int. J. Mol. Sci. 2024, 25(16), 9040; https://doi.org/10.3390/ijms25169040 - 20 Aug 2024
Viewed by 757
Abstract
It has been unequivocally established that kynurenic acid has a number of actions in a variety of cells and tissues, raising, in principle, the possibility of targeting its generation, metabolism or sites of action to manipulate those effects to a beneficial therapeutic end. [...] Read more.
It has been unequivocally established that kynurenic acid has a number of actions in a variety of cells and tissues, raising, in principle, the possibility of targeting its generation, metabolism or sites of action to manipulate those effects to a beneficial therapeutic end. However, many basic aspects of the biology of kynurenic acid remain unclear, potentially leading to some confusion and misinterpretations of data. They include questions of the source, generation, targets, enzyme expression, endogenous concentrations and sites of action. This essay is intended to raise and discuss many of these aspects as a source of reference for more balanced discussion. Those issues are followed by examples of situations in which modulating and correcting kynurenic acid production or activity could bring significant therapeutic benefit, including neurological and psychiatric conditions, inflammatory diseases and cell protection. More information is required to obtain a clear overall view of the pharmacological environment relevant to kynurenic acid, especially with respect to the active concentrations of kynurenine metabolites in vivo and changed levels in disease. The data and ideas presented here should permit a greater confidence in appreciating the sites of action and interaction of kynurenic acid under different local conditions and pathologies, enhancing our understanding of kynurenic acid itself and the many clinical conditions in which manipulating its pharmacology could be of clinical value. Full article
(This article belongs to the Special Issue Kynurenic Acid: Emerging Research Advances and Therapeutic Implications)
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19 pages, 981 KiB  
Review
Role of Kynurenine and Its Derivatives in the Neuroimmune System
by Makoto Fujikawa, Masashi Ueda and Kenta Maruyama
Int. J. Mol. Sci. 2024, 25(13), 7144; https://doi.org/10.3390/ijms25137144 - 28 Jun 2024
Viewed by 760
Abstract
In recent years, there has been a growing realization of intricate interactions between the nervous and immune systems, characterized by shared humoral factors and receptors. This interplay forms the basis of the neuroimmune system, the understanding of which will provide insights into the [...] Read more.
In recent years, there has been a growing realization of intricate interactions between the nervous and immune systems, characterized by shared humoral factors and receptors. This interplay forms the basis of the neuroimmune system, the understanding of which will provide insights into the pathogenesis of neurological diseases, in which the involvement of the immune system has been overlooked. Kynurenine and its derivatives derived from tryptophan have long been implicated in the pathogenesis of various neurological diseases. Recent studies have revealed their close association not only with neurological disorders but also with sepsis-related deaths. This review provides an overview of the biochemistry of kynurenine and its derivatives, followed by a discussion of their role via the modulation of the neuroimmune system in various diseases. Full article
(This article belongs to the Special Issue Kynurenic Acid: Emerging Research Advances and Therapeutic Implications)
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36 pages, 1808 KiB  
Review
Kynurenic Acid/AhR Signaling at the Junction of Inflammation and Cardiovascular Diseases
by Alevtina Y. Grishanova and Maria L. Perepechaeva
Int. J. Mol. Sci. 2024, 25(13), 6933; https://doi.org/10.3390/ijms25136933 - 25 Jun 2024
Viewed by 1088
Abstract
Persistent systemic chronic inflammatory conditions are linked with many pathologies, including cardiovascular diseases (CVDs), a leading cause of death across the globe. Among various risk factors, one of the new possible contributors to CVDs is the metabolism of essential amino acid tryptophan. Proinflammatory [...] Read more.
Persistent systemic chronic inflammatory conditions are linked with many pathologies, including cardiovascular diseases (CVDs), a leading cause of death across the globe. Among various risk factors, one of the new possible contributors to CVDs is the metabolism of essential amino acid tryptophan. Proinflammatory signals promote tryptophan metabolism via the kynurenine (KYN) pathway (KP), thereby resulting in the biosynthesis of several immunomodulatory metabolites whose biological effects are associated with the development of symptoms and progression of various inflammatory diseases. Some participants in the KP are agonists of aryl hydrocarbon receptor (AhR), a central player in a signaling pathway that, along with a regulatory influence on the metabolism of environmental xenobiotics, performs a key immunomodulatory function by triggering various cellular mechanisms with the participation of endogenous ligands to alleviate inflammation. An AhR ligand with moderate affinity is the central metabolite of the KP: KYN; one of the subsequent metabolites of KYN—kynurenic acid (KYNA)—is a more potent ligand of AhR. Understanding the role of AhR pathway-related metabolites of the KP that regulate inflammatory factors in cells of the cardiovascular system is interesting and important for achieving effective treatment of CVDs. The purpose of this review was to summarize the results of studies about the participation of the KP metabolite—KYNA—and of the AhR signaling pathway in the regulation of inflammation in pathological conditions of the heart and blood vessels and about the possible interaction of KYNA with AhR signaling in some CVDs. Full article
(This article belongs to the Special Issue Kynurenic Acid: Emerging Research Advances and Therapeutic Implications)
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0 pages, 1073 KiB  
Review
Implications of Kynurenine Pathway Metabolism for the Immune System, Hypothalamic–Pituitary–Adrenal Axis, and Neurotransmission in Alcohol Use Disorder
by Bartosz Osuch, Tomasz Misztal, Kinga Pałatyńska and Dorota Tomaszewska-Zaremba
Int. J. Mol. Sci. 2024, 25(9), 4845; https://doi.org/10.3390/ijms25094845 - 29 Apr 2024
Viewed by 1059
Abstract
In recent years, there has been a marked increase in interest in the role of the kynurenine pathway (KP) in mechanisms associated with addictive behavior. Numerous reports implicate KP metabolism in influencing the immune system, hypothalamic–pituitary–adrenal (HPA) axis, and neurotransmission, which underlie the [...] Read more.
In recent years, there has been a marked increase in interest in the role of the kynurenine pathway (KP) in mechanisms associated with addictive behavior. Numerous reports implicate KP metabolism in influencing the immune system, hypothalamic–pituitary–adrenal (HPA) axis, and neurotransmission, which underlie the behavioral patterns characteristic of addiction. An in-depth analysis of the results of these new studies highlights interesting patterns of relationships, and approaching alcohol use disorder (AUD) from a broader neuroendocrine–immune system perspective may be crucial to better understanding this complex phenomenon. In this review, we provide an up-to-date summary of information indicating the relationship between AUD and the KP, both in terms of changes in the activity of this pathway and modulation of this pathway as a possible pharmacological approach for the treatment of AUD. Full article
(This article belongs to the Special Issue Kynurenic Acid: Emerging Research Advances and Therapeutic Implications)
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