Does kynurenic acid act on nicotinic receptors? An assessment of the evidence

Abstract

As a major metabolite of kynurenine in the oxidative metabolism of tryptophan, kynurenic acid is of considerable biological and clinical importance as an endogenous antagonist of glutamate in the central nervous system. It is most active as an antagonist at receptors sensitive to N‐methyl‐D‐aspartate (NMDA) which regulate neuronal excitability and plasticity, brain development and behaviour. It is also thought to play a causative role in hypo‐glutamatergic conditions such as schizophrenia, and a protective role in several neurodegenerative disorders, notably Huntington’s disease. An additional hypothesis, that kynurenic acid could block nicotinic receptors for acetylcholine in the central nervous system has been proposed as an alternative mechanism of action of kynurenate. However, the evidence for this alternative mechanism is highly controversial, partly because at least eight earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and five subsequent, independent studies designed to repeat the results have failed to do so. Many studies considered to support the alternative ‘nicotinic’ hypothesis have been based on the use of analogs of kynurenate such as 7‐chloro‐kynurenic acid, or putatively nicotinic modulators such as galantamine, but a detailed analysis of the pharmacology of these compounds suggests that the results have often been misinterpreted, especially since the pharmacology of galantamine itself has been disputed. This review examines the evidence in detail, with the conclusion that there is no confirmed, reliable evidence for an antagonist activity of kynurenic acid at nicotinic receptors. Therefore, since there is overwhelming evidence for kynurenate acting at ionotropic glutamate receptors, especially NMDAR glutamate and glycine sites, with some activity at GPR35 sites and Aryl Hydrocarbon Receptors, results with kynurenic acid should be interpreted only in terms of these confirmed sites of action.

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

“…KYNA was reported to inhibit the presynaptic α7 nicotinic Ach receptors (IC 50 =~7 µM), but it has not been confirmed by an in vivo study. More evidences support the view that KYNA may not influence nicotinic Ach receptors [45,111]. Furthermore, KYNA exhibits a dual effect at AMPA receptors in a dose-dependent manner: KYNA inhibits at micromolar concentrations, but at nanomolar concentrations, it evokes facilitation through allosteric modulation of the AMPA receptor [112].…”

“…KYNA is an antagonist at ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), NMDA, kainate glutamate receptors, and the α7 nicotinic Ach receptor [44]. However, the role of KYNA at the α7 nicotinic Ach receptor remains controversial [45]. KYNA binds to the G protein-coupled receptor (GPR) 35 (GPR35) expressed in glia, macrophages, and monocytes to reduce glutamate release in brain and pro-inflammatory cytokine release in cell lines.…”

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…One issue which has aroused controversy in this area is a claim that the role of kynurenic acid in schizophrenia could involve the block of nicotinic receptors in addition to NMDA receptors. While the levels of kynurenic acid are increased in the CNS and probably contribute to the symptoms of schizophrenia (146) and other CNS disorders involving defective cognition, that claim has not been substantiated and cannot be replicated [see (158)]. Any apparent effect of kynurenic acid on nicotinic receptors appears to be secondary to the effects of nicotinic receptors on the release of glutamate and other neuroactive compounds (158).…”

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

“…The micromolar concentrations are inhibitory, while the nanomolar concentrations are facilitatory by allosteric modulation of the AMPA receptor [100,101]. The actions of KYNA at the α-7 nicotinic acetylcholine receptor are controversial [102]. KYNA reduces glutamate release by binding to the G-protein-coupled receptor 35 (GPR35) in the microglial cells, macrophages, and monocytes to [94].…”