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Flavonoids as positive allosteric modulators of α7 nicotinic receptors.

Authors :
Nielsen BE
Bermudez I
Bouzat C
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.)

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