concept

Kynurenic acid

Kynurenic acid (KYNA) is a bioactive compound that is produced along the kynurenine pathway (KP) during tryptophan degradation. In a few decades, KYNA shifted from being regarded a poorly characterized by-product of the KP to being considered a main player in many aspects of mammalian physiology, including the control of glutamatergic and cholinergic synaptic transmission, and the coordination of immunomodulation. The renewed attention being paid to the study of KYNA homeostasis is justified by the discovery of selective and potent inhibitors of kynurenine aminotransferase II, which is considered the main enzyme responsible for KYNA synthesis in the mammalian brain. Kynurenic acid (KYNA) is considered a “Janus-faced” compound in brain physiology (Rózsa et al., 2008; Wirthgen et al., 2018). In fact, KYNA limits the neurotoxicity associated with the action of excitatory amino acids (Birch et al., 1988) by acting as an endogenous antagonist at the glycine co-agonist site of the N-methyl-D-aspartate receptor (NMDAR). In addition, KYNA non-competitively antagonizes the α7-nicotinic acetylcholine receptor (α7nAChR) (Alkondon et al., 2004; Albuquerque and Schwarcz, 2013), modulating important neurophysiological processes. Moreover, KYNA plays a role as a direct reactive oxygen species (ROS) scavenger. On the other hand, abnormally high KYNA levels have been detected in biological samples from patients with schizophrenia (Erhardt et al., 2007; Sathyasaikumar et al., 2011), and the pharmacological elevation of KYNA concentrations in the CNS correlates with cognitive deficits (Chess et al., 2007). These observations point to KYNA as an important player in the onset and progression of neurological and psychiatric diseases that are associated with impaired glutamatergic and/or cholinergic neurotransmission (Stone and Darlington, 2013; Fujigaki et al., 2017). Moreover, KYNA is an agonist of the broadly expressed G protein-coupled receptor 35 (GPR35) (Wang et al., 2006) and the aryl hydrocarbon receptor (AhR) (DiNatale et al., 2010), which are involved in immunomodulation processes (Wirthgen et al., 2018). Taken as a whole, these studies disclose the multiplicity of biological actions of KYNA inside and outside the CNS (Figure 1B).

Ref:
Rossi F, Miggiano R, Ferraris DM and Rizzi M (2019) The Synthesis of Kynurenic Acid in Mammals: An Updated Kynurenine Aminotransferase Structural KATalogue. Front. Mol. Biosci. 6:7. doi: 10.3389/fmolb.2019.00007

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Added on Sep 3, 2022 by Barbara Van De Keer
Edited on Mar 4, 2023 by Barbara Van De Keer

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