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Kynurenic acid: translational perspectives of a therapeutically targetable gliotransmitter

Neuropsychopharmacology volume 49, pages 307–308 (2024)Cite this article

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Emerging clinical and pre-clinical evidence indicates that increased kynurenic acid (KYNA) formation, through the kynurenine pathway of tryptophan degradation, during critical life stages may contribute to neuropathological adversity and increased risk of neuropsychiatric illness. Targeting KYNA formation may help overcome underlying endophenotypes including cognition and arousal, thus there is a compelling need to develop novel therapeutic means to reduce brain KYNA.

The kynurenine pathway is stimulated by physiological perturbations, including immune activation, excessive stress, sleep loss, or obstetric complications. Activation of tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) increases kynurenine, which readily enters the brain. Kynurenine is metabolized by kynurenine 3-monooxygenase (KMO) to 3-hydroxykynurenine and eventually quinolinic acid (QUIN), or kynurenine aminotransferases (KAT I-IV) to KYNA within astrocytes [1]. An excess of central KYNA is found in patients with schizophrenia and bipolar disorder, suggesting KYNA may play a causative role in the illnesses [2, 3]. The clinically relevant increase in KYNA impacts neurotransmission, via mechanisms involving its antagonism of α7 nicotinic acetylcholine receptors (α7nACh-Rs) and N-methyl-d-aspartate receptors (NMDA-Rs) [1]. At these neuroactive sites, KYNA is postulated to modulate cognitive function, arousal, and sleep, which encompass endophenotypic attributes related to disrupted mental health.

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Fig. 1: Simplified representation of kynurenic acid (KYNA) formation and function in the brain.

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Funding

Funding

This work is supported by National Institutes of Health Grant Nos. NIH P50 MH103222 (AP), R21 AG080335 (AP), and Swedish Medical Research Council Grant Number 2021-02251 (SE), the Swedish Brain Foundation Grant Number FO2023-0333 (SE) and Ã…hlens-stiftelsen (SE).

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Authors and Affiliations

  1. Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA

    Ana Pocivavsek

  2. Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

    Sophie Erhardt

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  1. Ana Pocivavsek
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  2. Sophie Erhardt
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AP and SE drafted, edited, and approved the final paper.

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Correspondence to Ana Pocivavsek.

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Dr AP and Dr SE declare no potential competing interests.

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Pocivavsek, A., Erhardt, S. Kynurenic acid: translational perspectives of a therapeutically targetable gliotransmitter. Neuropsychopharmacol. 49, 307–308 (2024). https://doi.org/10.1038/s41386-023-01681-6

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