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

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

Publication date: Nov 06, 2019

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 CNS 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 8 earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and 5 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 mis-interpreted, 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 inotropic 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.

Stone, T.W. Does kynurenic acid act on nicotinic receptors? An assessment of the evidence. 06751. 2019 J Neurochem.

Concepts Keywords
Acetylcholine Protective neurodegenerative disorders
Antagonist Disease
Aspartate Branches of biology
Brain Organic compounds
Causative Neurochemistry
Central Nervous System NMDA receptor antagonists
Endogenous Ion channels
Galantamine Neurotransmitters
Glutamate Cell signaling
Glutamatergic Kynurenic acid
Glycine Glutamate receptor
Huntington N-Methyl-D-aspartic acid
Inotropic GPR35
Neurodegenerative Disorders
Nicotinic Receptors
Oxidative Metabolism


Type Source Name
drug DRUGBANK Kynurenic Acid
disease MESH tryptophan
drug DRUGBANK L-Tryptophan
drug DRUGBANK Ketamine
disease MESH schizophrenia
disease DOID schizophrenia
disease MESH neurodegenerative disorders
drug DRUGBANK Acetylcholine
drug DRUGBANK Galantamine
drug DRUGBANK Glycine

Original Article

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