Journal
NEUROPHARMACOLOGY
Volume 160, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2019.107794
Keywords
Nicotinic receptor; Patch-clamp; Single-channel recordings; Flavonoids; Cys-loop receptors
Categories
Funding
- Universidad Nacional del Sur [PGI 24/B227]
- Agencia Nacional de PromociOn Cientifica y Tecnologica [PICT-2015 0941, PICT-2017 1170]
- Oxford Brookes University
- Company of Biologists [JCSTF-180207]
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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.
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