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Flavonoids as positive allosteric modulators of α7 nicotinic receptors.
- Source :
-
Neuropharmacology [Neuropharmacology] 2019 Dec 01; Vol. 160, pp. 107794. Date of Electronic Publication: 2019 Sep 24. - Publication Year :
- 2019
-
Abstract
- The use of positive allosteric modulators (PAM) of α7 nicotinic receptors is a promising therapy for neurodegenerative, inflammatory and cognitive disorders. Flavonoids are polyphenolic compounds showing neuroprotective, anti-inflammatory and pro-cognitive actions. Besides their well-known antioxidant activity, flavonoids trigger intracellular pathways and interact with receptors, including α7. To reveal how the beneficial actions of flavonoids are linked to α7 function, we evaluated the effects of three representative flavonoids -genistein, quercetin and the neoflavonoid 5,7-dihydroxy-4-phenylcoumarin- on whole-cell and single-channel currents. All flavonoids increase the maximal currents elicited by acetylcholine with minimal effects on desensitization and do not reactivate desensitized receptors, a behaviour consistent with type I PAMs. At the single-channel level, they increase the duration of the open state and produce activation in long-duration episodes with a rank order of efficacy of genistein > quercetin ≥ neoflavonoid. By using mutant and chimeric α7 receptors, we demonstrated that flavonoids share transmembrane structural determinants with other PAMs. The α7-PAM activity of flavonoids results in decreased cell levels of reactive oxygen species. Thus, allosteric potentiation of α7 may be an additional mechanism underlying neuroprotective actions of flavonoids, which may be used as scaffolds for designing new therapeutic agents.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Acetylcholine pharmacology
Allosteric Regulation drug effects
Animals
Cell Line
Coumarins pharmacology
Female
Flavonoids metabolism
Genistein pharmacology
Humans
Inflammation drug therapy
Nervous System Diseases drug therapy
Quercetin pharmacology
Reactive Oxygen Species metabolism
Xenopus laevis
alpha7 Nicotinic Acetylcholine Receptor metabolism
Flavonoids pharmacology
Nicotinic Agonists pharmacology
alpha7 Nicotinic Acetylcholine Receptor drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 160
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 31560909
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2019.107794