Flavonoids as positive allosteric modulators of α7 nicotinic receptors

[摘要] The use of positive allosteric modulators (PAM) of alpha 7 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 alpha 7. To reveal how the beneficial actions of flavonoids are linked to alpha 7 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 alpha 7 receptors, we demonstrated that flavonoids share transmembrane structural determinants with other PAMs. The alpha 7-PAM activity of flavonoids results in decreased cell levels of reactive oxygen species. Thus, allosteric potentiation of alpha 7 may be an additional mechanism underlying neuroprotective actions of flavonoids, which may be used as scaffolds for designing new therapeutic agents.

[发布日期] 2019-12-01

[关键词] Nicotinic receptor;Patch-clamp;Single-channel recordings;Flavonoids;Cys-loop receptors