Does kynurenic acid act on nicotinic receptors? An assessment of the evidence
| Autor: | Trevor W. Stone |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
nicotinic receptors Review Nicotinic Antagonists Receptors Nicotinic Pharmacology Kynurenic Acid Kynurenate NMDA receptors Receptors N-Methyl-D-Aspartate Biochemistry Receptors G-Protein-Coupled 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Kynurenic acid medicine Animals Humans Receptor Brain Chemistry Binding Sites Galantamine Chemistry Glutamate receptor Brain Reproducibility of Results kynurenine 030104 developmental biology Nicotinic agonist Receptors Aryl Hydrocarbon cholinergic receptors NMDA receptor 030217 neurology & neurosurgery Acetylcholine Kynurenine medicine.drug |
| Zdroj: | Journal of Neurochemistry |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/jnc.14907 |
| Popis: | 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. Kynurenic acid has well‐established activity as an antagonist at glutamate receptors, especially the glutamate and glycine co‐agonist binding sites, with possibly relevant actions on Aryl Hydrocarbon Receptors and the GPR35 binding site. A single proposal that it also acts on acetylcholine nicotinic receptors is analysed and discussed in the light of at least 12 failures to reproduce the activity, and a wide range of pharmacological arguments. It is concluded that there is no confirmed, reliable evidence for any effect at nicotinic acetylcholine receptors. |
| Databáze: | OpenAIRE |
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