The alpha7 nicotinic acetylcholine receptor (nAChR) is a potential target in neuroinflammation. Screening a plant extract library identified Solidago nemoralis as containing methyl-quercetin derivatives that are relatively selective ligands for the alpha7 nAChR. Flavonoids are not known for this activity, so we screened a small library of pure flavonoids to confirm our findings. Some flavonoids, e.g. rhamnetin, displaced a selective alpha7 nAChR radioligand from rat brain membranes whereas similar structures e.g. sakuranetin, did not. To evaluate the contribution of this putative nAChR activity to the known anti-inflammatory properties of these flavonoids, we compared their effects on lipopolysaccharide induced release of inflammatory mediators from BV2 microglia. Both rhamnetin and sakuranetin reduced mediator release, but differed in potency (rhamnetin > sakuranetin) and the Hill slope of their concentration-response curves. For rhamnetin the Hill coefficient was > 3.0 whereas for sakuranetin the coefficient was 1.0, suggesting that effects of rhamnetin are mediated through more than one mechanism, whereas sakuranetin has a single mechanism. nAChR antagonists decreased the Hill coefficient for rhamnetin toward unity, which suggests that a nAChR-mediated mechanism contributes cooperatively to its overall anti-inflammatory effect. In contrast nAChR antagonists had no effect on the potency or Hill coefficient for sakuranetin, but a concentration of nicotine (1 μM) that had no effect alone, significantly increased the Hill coefficient of this flavonoid. In conclusion, the anti-inflammatory effects of rhamnetin benefit cooperatively from a nAChR-mediated mechanism. This action, together with potent free radical scavenging activity, suggests that flavonoids with alpha7 nAChR activity have therapeutic potential in neuroinflammatory conditions.
|Number of pages||11|
|State||Published - Oct 2014|
Bibliographical noteFunding Information:
This work was supported in part by NIAAA ( National Institute on Alcohol Abuse and Alcoholism ) grants ( R21-AA020188 , R42-AA014555 , and R42-AA015475 ) awarded to Dr. Littleton as Principal Investigator. The authors would like to thank Dr. Linda Van Eldik from the Sanders Brown Center on Aging at the University of Kentucky for providing BV2 microglia.
- Drug discovery
- Nicotinic acetylcholine receptors
- Solidago nemoralis
ASJC Scopus subject areas
- Drug Discovery