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Kynurenic Acid: Emerging Research Advances and Therapeutic Implications

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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: 31 May 2024 | Viewed by 2524

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Special Issue Editors

Prof. Dr. Piotr Paluszkiewicz

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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

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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

Manuscript Submission Information

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Keywords

kynurenic acid
kynurenine pathway
kynurenine
therapeutic use
supply and distribution

Published Papers (3 papers)

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Research

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24 pages, 14594 KiB

Open AccessArticle

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

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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 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

Open AccessArticle

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

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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 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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18 pages, 1072 KiB

Open AccessReview

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

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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 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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