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

Trevor W Stone

doi:10.1111/jnc.14907

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.

Highlights

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
The authors subsequently suggested that this effect was mediated indirectly via nicotinic receptors (Moriguchi et al 2009a), their earlier experiments seem to have been conducted in the absence of an NMDA receptor blocker, since 2-amino-5-phosphono-pentanoic acid was used only to confirm the NMDAR-dependency of long-term potentiation (LTP) but was not included in the experiments on galantamine
The results showed that galantamine does potentiate NMDA-dependent LTP induced by a theta-stimulation protocol, confirming that the drug could reverse or antagonise an effect produced by blocking NMDA receptors in the presence of nicotinic receptor blockade

Summary

Introduction

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. The concentrations of kynurenic acid needed to reduce nicotinic transmission (EC50 136lM), were similar to those which block NMDA receptors – similar to those reported by Hilmas et al (2001) in slices but orders of magnitude greater than those claimed to work in cell cultures (Hilmas et al 2001).

Results

Conclusion